Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-IA22
L. Casciola‐Rosen, Ami A. Shah, A. Rosen
Some rheumatic disease autoantibodies are powerful markers of subgroups of patients who have distinct disease phenotypes and trajectories. Of particular interest are markers of several disease subgroups in whom cancer and rheumatic disease onset are clustered together in time. For example, a subgroup of scleroderma patients have coincident onset of cancer and scleroderma. This is observed in scleroderma patients with autoantibodies against RNA polymerase-3 (POLR3), and more recently with autoantibodies recognizing the minor spliceosome. In autoimmune myopathies, temporal clustering of diagnosis of cancer and myositis is associated with autoantibodies to NXP2 and components of the TIF1 complex. Interestingly, although the incidence of cancer is higher in patients with these autoantibodies, most patients with these autoantibodies do not manifest cancer, even with extended periods of follow-up. These observations provide an important opportunity to investigate the potential mechanisms which operate at the cancer-immune interface during development of rheumatic diseases. In cancers from anti-POLR3-positive scleroderma patients with a short scleroderma-cancer interval, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to POLR3 but not in eight patients without these antibodies. 3 antibody-positive patients had somatic mutations in POLR3A; 5 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. In a larger scleroderma cohort (>2300 patients), the incidence of cancer in various autoantibody subgroups was compared to data from the Surveillance, Epidemiology and End Results (SEER) Program. An increase in cancer incidence in scleroderma patients with POLR3 autoantibodies was observed compared to the general population; strikingly, patients with anti-centromere autoantibodies had a lower cancer incidence than observed in the general population. The finding that distinct serologic subgroups have different cancer risks suggests that cancer immunity may be a common principle across the scleroderma spectrum, with cancer emergence influenced by the effectiveness of the different immune responses. For example, in scleroderma patients with anti-centromere antibodies, cancer emergence may be inhibited, while inhibition of cancer emergence may only be partial for anti-POLR3. Prior studies in small cohorts of breast cancer patients have demonstrated that anti-centromere antibodies may be present, and may associate with improved disease-free and overall survival. Additionally, recent data also suggest that anti-DNA antibodies can have direct anti-cancer effects in cells with DNA repair defects, possibly explaining the decreased risk of breast and other cancers observed among patients with SLE.Taken together, these data suggest that at least some patients with autoimmune rheu
一些风湿病自身抗体是具有不同疾病表型和轨迹的患者亚群的有力标记。特别令人感兴趣的是癌症和风湿病发病在时间上聚集在一起的几个疾病亚群的标志物。例如，硬皮病患者的一个亚组有癌症和硬皮病的同时发病。这在患有抗RNA聚合酶-3 (POLR3)自身抗体的硬皮病患者中观察到，最近也有识别次要剪接体的自身抗体。在自身免疫性肌病中，癌症和肌炎诊断的时间聚类与NXP2和TIF1复合物成分的自身抗体相关。有趣的是，尽管这些自身抗体患者的癌症发病率较高，但大多数具有这些自身抗体的患者即使经过长时间的随访也没有表现出癌症。这些观察结果为研究风湿性疾病发展过程中癌症免疫界面的潜在机制提供了重要机会。在抗POLR3阳性的硬皮病患者的癌症中，我们发现POLR3A位点的遗传改变在8名有POLR3抗体的患者中有6名，而在8名没有这些抗体的患者中没有。3例抗体阳性患者POLR3A发生体细胞突变;5例患者POLR3A位点杂合性缺失。外周血淋巴细胞和血清分析表明，POLR3A突变引发细胞免疫和交叉反应性体液免疫反应。在一个更大的硬皮病队列(>2300例患者)中，不同自身抗体亚组的癌症发病率与来自监测、流行病学和最终结果(SEER)项目的数据进行了比较。与普通人群相比，患有POLR3自身抗体的硬皮病患者的癌症发病率增加;引人注目的是，抗着丝粒自身抗体患者的癌症发病率低于普通人群。不同的血清学亚组具有不同的癌症风险，这一发现表明，癌症免疫可能是整个硬皮病谱系的共同原则，癌症的出现受到不同免疫反应的有效性的影响。例如，在有抗着丝粒抗体的硬皮病患者中，癌症的出现可能被抑制，而抗polr3可能只是部分抑制癌症的出现。先前对乳腺癌患者小队列的研究表明，抗着丝粒抗体可能存在，并且可能与改善的无病生存期和总生存期有关。此外，最近的数据还表明，抗DNA抗体可以在具有DNA修复缺陷的细胞中具有直接的抗癌作用，这可能解释了SLE患者中乳腺癌和其他癌症风险降低的原因。综上所述，这些数据表明，至少一些自身免疫性风湿病(如硬皮病)患者可能代表了人类的天然癌症免疫编辑。在最简单的模型中，不同癌症中自身抗原的体细胞突变引发了对突变自身抗原的免疫反应，该突变自身抗原扩散到包括野生型自身抗原，并发挥抗癌作用，同时引起正常组织的损伤或功能障碍。了解在不同患者和亚组中抗癌效果范围的潜在机制可能为如何更有效地利用自身免疫性疾病的抗癌免疫反应提供重要见解。引文格式:Livia Casciola-Rosen, Ami Shah, Antony Rosen。自身免疫性风湿病与癌症[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要1 - 22。
{"title":"Abstract IA22: Autoimmune rheumatic diseases and cancer","authors":"L. Casciola‐Rosen, Ami A. Shah, A. Rosen","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA22","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA22","url":null,"abstract":"Some rheumatic disease autoantibodies are powerful markers of subgroups of patients who have distinct disease phenotypes and trajectories. Of particular interest are markers of several disease subgroups in whom cancer and rheumatic disease onset are clustered together in time. For example, a subgroup of scleroderma patients have coincident onset of cancer and scleroderma. This is observed in scleroderma patients with autoantibodies against RNA polymerase-3 (POLR3), and more recently with autoantibodies recognizing the minor spliceosome. In autoimmune myopathies, temporal clustering of diagnosis of cancer and myositis is associated with autoantibodies to NXP2 and components of the TIF1 complex. Interestingly, although the incidence of cancer is higher in patients with these autoantibodies, most patients with these autoantibodies do not manifest cancer, even with extended periods of follow-up. These observations provide an important opportunity to investigate the potential mechanisms which operate at the cancer-immune interface during development of rheumatic diseases. In cancers from anti-POLR3-positive scleroderma patients with a short scleroderma-cancer interval, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to POLR3 but not in eight patients without these antibodies. 3 antibody-positive patients had somatic mutations in POLR3A; 5 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. In a larger scleroderma cohort (>2300 patients), the incidence of cancer in various autoantibody subgroups was compared to data from the Surveillance, Epidemiology and End Results (SEER) Program. An increase in cancer incidence in scleroderma patients with POLR3 autoantibodies was observed compared to the general population; strikingly, patients with anti-centromere autoantibodies had a lower cancer incidence than observed in the general population. The finding that distinct serologic subgroups have different cancer risks suggests that cancer immunity may be a common principle across the scleroderma spectrum, with cancer emergence influenced by the effectiveness of the different immune responses. For example, in scleroderma patients with anti-centromere antibodies, cancer emergence may be inhibited, while inhibition of cancer emergence may only be partial for anti-POLR3. Prior studies in small cohorts of breast cancer patients have demonstrated that anti-centromere antibodies may be present, and may associate with improved disease-free and overall survival. Additionally, recent data also suggest that anti-DNA antibodies can have direct anti-cancer effects in cells with DNA repair defects, possibly explaining the decreased risk of breast and other cancers observed among patients with SLE.Taken together, these data suggest that at least some patients with autoimmune rheu","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83425402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A122
Sadeem Ahmad, X. Mu, S. Hur
Melanoma Differentiation Associated Gene-5 (MDA5) is an innate immune receptor that binds to viral double-stranded RNAs (dsRNAs) and initiates type I and III interferon signaling cascade thereby playing a key role in antiviral immune response. Recently, a number of mutations that lead to aberrant activation of MDA5 have been implicated in various autoinflammatory disorders including Aicardi-Goutieres syndrome. The mechanistic basis of this constitutive MDA5 activation, however, has remained elusive. An understanding of the subtle balance of self vs. non-self discrimination by MDA5 is important, especially in the context of recent reports demonstrating the targeted activation of MDA5 as a potential therapeutic strategy against diverse carcinoma. Our work revealed a hitherto unknown role played by the RNA-rich cellular environment in preventing aberrant MDA5 activation by imposing cooperative filament assembly on dsRNAs as a functional requirement for signal activation. We further employed a novel RNase protection-RNAseq approach to show that the disease-causing gain-of-function (GOF) mutants of MDA5 can form signaling-competent filaments on endogenous RNA populations comprising mainly Alu RNA duplexes. Strikingly, under physiologic conditions, the wild type MDA5 is not activated by Alu RNAs because of its sensitivity to structural irregularities such as bulges and mismatches commonly occurring in Alu:Alu hybrids. The GOF mutants, on the other hand, show reduced sensitivity to disruptions in duplex RNA structures as revealed by our in-depth biochemical probing. Overall, the work reveals the underlying mechanism behind MDA5-mediated inflammatory disorders. Moreover, it highlights the unique role played by Alu RNAs as an evolutionary tether on MDA5, keeping its affinity towards “self” ligands under check during the course of evolution. Citation Format: Sadeem Ahmad, Xin Mu, Sun Hur. Self-recognition of Alu duplex RNAs is the basis for MDA5-mediated interferonopathies [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A122.
{"title":"Abstract A122: Self-recognition of Alu duplex RNAs is the basis for MDA5-mediated interferonopathies","authors":"Sadeem Ahmad, X. Mu, S. Hur","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A122","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A122","url":null,"abstract":"Melanoma Differentiation Associated Gene-5 (MDA5) is an innate immune receptor that binds to viral double-stranded RNAs (dsRNAs) and initiates type I and III interferon signaling cascade thereby playing a key role in antiviral immune response. Recently, a number of mutations that lead to aberrant activation of MDA5 have been implicated in various autoinflammatory disorders including Aicardi-Goutieres syndrome. The mechanistic basis of this constitutive MDA5 activation, however, has remained elusive. An understanding of the subtle balance of self vs. non-self discrimination by MDA5 is important, especially in the context of recent reports demonstrating the targeted activation of MDA5 as a potential therapeutic strategy against diverse carcinoma. Our work revealed a hitherto unknown role played by the RNA-rich cellular environment in preventing aberrant MDA5 activation by imposing cooperative filament assembly on dsRNAs as a functional requirement for signal activation. We further employed a novel RNase protection-RNAseq approach to show that the disease-causing gain-of-function (GOF) mutants of MDA5 can form signaling-competent filaments on endogenous RNA populations comprising mainly Alu RNA duplexes. Strikingly, under physiologic conditions, the wild type MDA5 is not activated by Alu RNAs because of its sensitivity to structural irregularities such as bulges and mismatches commonly occurring in Alu:Alu hybrids. The GOF mutants, on the other hand, show reduced sensitivity to disruptions in duplex RNA structures as revealed by our in-depth biochemical probing. Overall, the work reveals the underlying mechanism behind MDA5-mediated inflammatory disorders. Moreover, it highlights the unique role played by Alu RNAs as an evolutionary tether on MDA5, keeping its affinity towards “self” ligands under check during the course of evolution. Citation Format: Sadeem Ahmad, Xin Mu, Sun Hur. Self-recognition of Alu duplex RNAs is the basis for MDA5-mediated interferonopathies [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A122.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83243288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A138
J. Koh, K. Lee, Bo-Ryun Kim, Mi Soon Kim, H. Cho, Jong-Mu Sun, J. Ahn, Keunchil Park, M. Ahn
Background: The factors in tumor microenvironment hinder T-cell activities against tumor cells. The major immunosuppressive cells in tumor sites are myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T (Treg) cell, and the effector molecules released by those immunosuppressive cells also regulate T-cell activities. Therefore, in this study we examined the pattern of immunosuppressive cells in patients with non-small cell lung cancer. Then, we tested T-cell activities to verify whether the suppressive immune cell populations can influence T-cell activity by monitoring T-cell exhaustion markers. Since CD39 and CD73 expression on cytotoxic T-cell are known to be T-cell exhaustion markers, we analyzed CD39 and CD73 on CD8+ T-cells. Method: Baseline and one week after anti-PD-1 immunotherapy (pembrolizumab and nivolumab) blood samples (n=81) were collected (stage III and IV). For the correlation of suppressive immune cells with disease progression, baseline blood samples from the patients (n=59, stage I~IV) and healthy donors (n=21) were collected. Granulocytic-MDSC, Monocytic-MDSC, TAM, Treg, and CD39+ and CD73+ cytotoxic T-cell population from patients’ PBMC (n=81 and n=59) were analyzed by FACS Verse. For the suppressive assay, isolated T-cells were activated with anti-CD3 and anti-CD28 and then MDSC was co-cultured with T-cells for a week followed by Ki-67, CD39 and CD73 analysis by FACS Verse. Results: G-MDSC (p-value=0.0023), M-MDSC (p-value=0.0032), TAM ((p
{"title":"Abstract A138: CD39 increase on cytotoxic T-cell induced by myeloid-derived suppressor cell correlated with poor prognosis in patients with non-small cell lung cancer","authors":"J. Koh, K. Lee, Bo-Ryun Kim, Mi Soon Kim, H. Cho, Jong-Mu Sun, J. Ahn, Keunchil Park, M. Ahn","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A138","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A138","url":null,"abstract":"Background: The factors in tumor microenvironment hinder T-cell activities against tumor cells. The major immunosuppressive cells in tumor sites are myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T (Treg) cell, and the effector molecules released by those immunosuppressive cells also regulate T-cell activities. Therefore, in this study we examined the pattern of immunosuppressive cells in patients with non-small cell lung cancer. Then, we tested T-cell activities to verify whether the suppressive immune cell populations can influence T-cell activity by monitoring T-cell exhaustion markers. Since CD39 and CD73 expression on cytotoxic T-cell are known to be T-cell exhaustion markers, we analyzed CD39 and CD73 on CD8+ T-cells. Method: Baseline and one week after anti-PD-1 immunotherapy (pembrolizumab and nivolumab) blood samples (n=81) were collected (stage III and IV). For the correlation of suppressive immune cells with disease progression, baseline blood samples from the patients (n=59, stage I~IV) and healthy donors (n=21) were collected. Granulocytic-MDSC, Monocytic-MDSC, TAM, Treg, and CD39+ and CD73+ cytotoxic T-cell population from patients’ PBMC (n=81 and n=59) were analyzed by FACS Verse. For the suppressive assay, isolated T-cells were activated with anti-CD3 and anti-CD28 and then MDSC was co-cultured with T-cells for a week followed by Ki-67, CD39 and CD73 analysis by FACS Verse. Results: G-MDSC (p-value=0.0023), M-MDSC (p-value=0.0032), TAM ((p","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80840402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A131
F. Heubach, P. Schlegel, L. Zekri, Timo Manz, S. Schleicher, A. Rabsteyn, G. Jung, H. Bühring, S. Gillies, R. Handgretinger, P. Lang
Introduction: Targeting disialoganglioside GD2 with monoclonal antibodies (mAbs) significantly improves survival in high-risk neuroblastoma (NB) patients after autologous or allogeneic SCT. However, GD2 expression is heterogeneous and the recently approved anti-GD2 mAb CH14.18 causes severe adverse effects, e.g., neuropathy and neuropathic pain due to neurotoxicity. Additional or alternative target antigens might improve therapy. B7-H3 belongs to the B7-CD28 family and is thought to function as an immune checkpoint by regulating T and NK cell response. B7-H3 is highly overexpressed on many solid tumors, correlating with poor prognosis and outcome. However, on healthy tissue its protein expression is very limited, thus making B7-H3 an interesting target for cancer immunotherapy. Therefore, we evaluated the use of B7-H3 as an alternative to GD2 and investigated different anti-B7-H3 mAb constructs and mAb-cytokine fusions (immunocytokines) for their ability to elicit antibody-dependenT-cellular cytotoxicity (ADCC). Methods: Derived from a parent anti-B7-H3 clone (HEK5-1B3), five additional mAb constructs were engineered: (1) chimeric with human IL-2 fusion (cHEK5-IL2), (2) chimeric and Fc-optimized (SDIE) w/o fusion (cHEK5opt), (3) cHEK5opt fused with human IL-2 (cHEK5opt-IL2), (4) cHEK5opt fused with human IL-15 (cHEK5opt-IL15), and (5) cHEK5-IL2 produced in rat myeloma YB2/0 to create an optimized low-fucose version (cHEX5LF-IL2). All IL-2 fusions were to the C-terminus of the light chain. The abilities of all six anti-B7-H3 mAb constructs and the GD2-specific mAb CH14.18 to mediate ADCC were compared in vitro in cytotoxicity assays using calcein release assays and the RTCA xCELLigence system. TargeT-cells: NB cell lines expressing high levels of B7-H3 but variable levels of GD2 (LAN-1, Kelly, SH-SY5Y). Effector cells: Human expanded NK cells (eNKs), expanded γ/δ T-cells and patient PBMCs after allogeneic SCT. Results: Except the parent clone, all anti-B7-H3 mAb constructs were able to elicit ADCC. TargeT-cell lysis of LAN-1 (high expression of both GD2 and B7-H3) mediated by the optimized anti-B7-H3 immunocytokines was comparable or even better than that mediated by CH14.18 (effectors: eNKs; calculated after 36 hrs.; in ascending order): Targets + effectors w/o mAb (24 %), parent pHEK5 (29 %), cHEK5opt (44 %), cHEK5-IL2 (76 %), cHEK5opt-IL15 (85 %), CH14.18 (90 %) and cHEK5opt-IL2 (97 %). Recently, we produced the low-fucose immunocytokine cHEX5LF-IL2. In a direct comparison with all other mAb constructs the cHEX5LF-IL2 immunocytokine mediated best targeT-cell lysis against SH-SY5Y (effectors: eNKs; calculated after 48 hrs.; in ascending order): Targets + effectors w/o mAb (31 %), CH14.18 (42 %), parent pHEK5 (46 %), cHEK5-IL2 (80 %), cHEK5opt (85 %), cHEK5opt-IL2 (93 %), cHEK5opt-IL15 (96 %) and low-fucose cHEX5LF-IL2 (100 %). Using expanded γ/δ T-cells of healthy donors we were able to confirm cHEX5LF-IL2 to be the most effective anti-B7-H3 mAb
{"title":"Abstract A131: Targeting B7-H3 (CD276) in neuroblastoma: In vitro evaluation of Fc-optimized antibodies and immunocytokines","authors":"F. Heubach, P. Schlegel, L. Zekri, Timo Manz, S. Schleicher, A. Rabsteyn, G. Jung, H. Bühring, S. Gillies, R. Handgretinger, P. Lang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A131","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A131","url":null,"abstract":"Introduction: Targeting disialoganglioside GD2 with monoclonal antibodies (mAbs) significantly improves survival in high-risk neuroblastoma (NB) patients after autologous or allogeneic SCT. However, GD2 expression is heterogeneous and the recently approved anti-GD2 mAb CH14.18 causes severe adverse effects, e.g., neuropathy and neuropathic pain due to neurotoxicity. Additional or alternative target antigens might improve therapy. B7-H3 belongs to the B7-CD28 family and is thought to function as an immune checkpoint by regulating T and NK cell response. B7-H3 is highly overexpressed on many solid tumors, correlating with poor prognosis and outcome. However, on healthy tissue its protein expression is very limited, thus making B7-H3 an interesting target for cancer immunotherapy. Therefore, we evaluated the use of B7-H3 as an alternative to GD2 and investigated different anti-B7-H3 mAb constructs and mAb-cytokine fusions (immunocytokines) for their ability to elicit antibody-dependenT-cellular cytotoxicity (ADCC). Methods: Derived from a parent anti-B7-H3 clone (HEK5-1B3), five additional mAb constructs were engineered: (1) chimeric with human IL-2 fusion (cHEK5-IL2), (2) chimeric and Fc-optimized (SDIE) w/o fusion (cHEK5opt), (3) cHEK5opt fused with human IL-2 (cHEK5opt-IL2), (4) cHEK5opt fused with human IL-15 (cHEK5opt-IL15), and (5) cHEK5-IL2 produced in rat myeloma YB2/0 to create an optimized low-fucose version (cHEX5LF-IL2). All IL-2 fusions were to the C-terminus of the light chain. The abilities of all six anti-B7-H3 mAb constructs and the GD2-specific mAb CH14.18 to mediate ADCC were compared in vitro in cytotoxicity assays using calcein release assays and the RTCA xCELLigence system. TargeT-cells: NB cell lines expressing high levels of B7-H3 but variable levels of GD2 (LAN-1, Kelly, SH-SY5Y). Effector cells: Human expanded NK cells (eNKs), expanded γ/δ T-cells and patient PBMCs after allogeneic SCT. Results: Except the parent clone, all anti-B7-H3 mAb constructs were able to elicit ADCC. TargeT-cell lysis of LAN-1 (high expression of both GD2 and B7-H3) mediated by the optimized anti-B7-H3 immunocytokines was comparable or even better than that mediated by CH14.18 (effectors: eNKs; calculated after 36 hrs.; in ascending order): Targets + effectors w/o mAb (24 %), parent pHEK5 (29 %), cHEK5opt (44 %), cHEK5-IL2 (76 %), cHEK5opt-IL15 (85 %), CH14.18 (90 %) and cHEK5opt-IL2 (97 %). Recently, we produced the low-fucose immunocytokine cHEX5LF-IL2. In a direct comparison with all other mAb constructs the cHEX5LF-IL2 immunocytokine mediated best targeT-cell lysis against SH-SY5Y (effectors: eNKs; calculated after 48 hrs.; in ascending order): Targets + effectors w/o mAb (31 %), CH14.18 (42 %), parent pHEK5 (46 %), cHEK5-IL2 (80 %), cHEK5opt (85 %), cHEK5opt-IL2 (93 %), cHEK5opt-IL15 (96 %) and low-fucose cHEX5LF-IL2 (100 %). Using expanded γ/δ T-cells of healthy donors we were able to confirm cHEX5LF-IL2 to be the most effective anti-B7-H3 mAb","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77274161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A132
J. Hu, Xing Liu, Jingxia Zhao, S. Xia, J. Ruan, Xuemei Luo, Justin Kim, J. Lieberman, Hao Wu
Inflammasomes are multiprotein signaling scaffolds that assemble in response to invasive pathogens and sterile danger signals to activate inflammatory caspases (1/4/5/11), which trigger inflammatory death (pyroptosis) and processing and release of proinflammatory cytokines. Inflammasome activation contributes to many human diseases, including inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer’s disease, and sepsis, the often fatal response to systemic infection. The recent identification of the pore-forming protein gasdermin D (GSDMD) as the final pyroptosis executioner downstream of inflammasome activation presents an attractive drug target for these diseases. Here we show that C-23 and C-27 potently inhibit GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1β secretion in human and mouse cells. Moreover, C-23, administered at a clinically well-tolerated dose, inhibits LPS-induced septic death and IL-1β secretion in mice. Both compounds covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation. Inflammatory caspases employ Cys active sites, and many previously identified inhibitors of inflammatory mediators, including those against NLRP3 and NF-κB, covalently modify reactive cysteine residues. Since NLRP3 and noncanonical inflammasome activation are amplified by cellular oxidative stress, these redox-sensitive reactive cysteine residues may regulate inflammation endogenously, and compounds that covalently modify reactive cysteines may inhibit inflammation by acting at multiple steps. Indeed, both C-23 and C-27 also directly inhibit inflammatory caspases and pleiotropically suppress multiple processes in inflammation triggered by both canonical and noncanonical inflammasomes, including priming, puncta formation and caspase activation. Hence, cysteine-reactive compounds, despite their lack of specificity, may be attractive agents for reducing inflammation. Citation Format: Jun Hu, Xing Liu, Jingxia Zhao, Shiyu Xia, Jianbin Ruan, Xuemei Luo, Justin Kim, Judy Lieberman, Hao Wu. Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A132.
炎性小体是一种多蛋白信号传导支架，在病原体侵入和无菌危险信号的作用下组装，激活炎性半胱天冬酶(1/4/5/11)，引发炎性死亡(焦亡)和促炎细胞因子的加工和释放。炎性小体的激活导致了许多人类疾病，包括炎症性肠病、痛风、II型糖尿病、心血管疾病、阿尔茨海默病和败血症，败血症通常是对全身感染的致命反应。最近发现的成孔蛋白气皮蛋白D (GSDMD)作为炎性小体激活下游的最终焦亡刽子手，为这些疾病提供了一个有吸引力的药物靶点。本研究表明，C-23和C-27能有效抑制人和小鼠细胞中脂质体、炎性小体介导的焦亡和IL-1β分泌的GSDMD孔形成。此外，临床耐受良好剂量的C-23可抑制lps诱导的脓毒性死亡和小鼠IL-1β分泌。这两种化合物共价修饰一个保守的Cys(人类Cys191和小鼠GSDMD Cys192)，这对孔隙形成至关重要。炎性半胱氨酸酶利用胱氨酸活性位点，许多先前发现的炎症介质抑制剂，包括抗NLRP3和NF-κB的抑制剂，共价修饰活性半胱氨酸残基。由于NLRP3和非典型炎性体的激活被细胞氧化应激放大，这些氧化还原敏感的活性半胱氨酸残基可能内源性调节炎症，共价修饰活性半胱氨酸的化合物可能通过多个步骤抑制炎症。事实上，C-23和C-27还能直接抑制炎性半胱天冬酶，并多向抑制典型和非典型炎性小体引发的炎症的多个过程，包括启动、斑点形成和半胱天冬酶激活。因此，半胱氨酸反应性化合物尽管缺乏特异性，但可能是减轻炎症的有吸引力的药物。引用格式:胡军，刘星，赵敬霞，夏世玉，阮建斌，罗雪梅，Justin Kim, Judy Lieberman，吴昊。针对气真皮蛋白D中活性半胱氨酸的焦亡抑制剂鉴定[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫，2019;7(2增刊):摘要nr A132。
{"title":"Abstract A132: Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D","authors":"J. Hu, Xing Liu, Jingxia Zhao, S. Xia, J. Ruan, Xuemei Luo, Justin Kim, J. Lieberman, Hao Wu","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A132","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A132","url":null,"abstract":"Inflammasomes are multiprotein signaling scaffolds that assemble in response to invasive pathogens and sterile danger signals to activate inflammatory caspases (1/4/5/11), which trigger inflammatory death (pyroptosis) and processing and release of proinflammatory cytokines. Inflammasome activation contributes to many human diseases, including inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer’s disease, and sepsis, the often fatal response to systemic infection. The recent identification of the pore-forming protein gasdermin D (GSDMD) as the final pyroptosis executioner downstream of inflammasome activation presents an attractive drug target for these diseases. Here we show that C-23 and C-27 potently inhibit GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1β secretion in human and mouse cells. Moreover, C-23, administered at a clinically well-tolerated dose, inhibits LPS-induced septic death and IL-1β secretion in mice. Both compounds covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation. Inflammatory caspases employ Cys active sites, and many previously identified inhibitors of inflammatory mediators, including those against NLRP3 and NF-κB, covalently modify reactive cysteine residues. Since NLRP3 and noncanonical inflammasome activation are amplified by cellular oxidative stress, these redox-sensitive reactive cysteine residues may regulate inflammation endogenously, and compounds that covalently modify reactive cysteines may inhibit inflammation by acting at multiple steps. Indeed, both C-23 and C-27 also directly inhibit inflammatory caspases and pleiotropically suppress multiple processes in inflammation triggered by both canonical and noncanonical inflammasomes, including priming, puncta formation and caspase activation. Hence, cysteine-reactive compounds, despite their lack of specificity, may be attractive agents for reducing inflammation. Citation Format: Jun Hu, Xing Liu, Jingxia Zhao, Shiyu Xia, Jianbin Ruan, Xuemei Luo, Justin Kim, Judy Lieberman, Hao Wu. Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A132.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"205 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77481833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A147
D. Pereira, Benjamin J. Capoccia, R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. C. Wilson, P. Manning, R. Carr
Recent success in cancer immunotherapy has targeted immune checkpoints such as PD-1, PDL-1, and CTLA-4 to enhance the cytotoxic activity of the adaptive T-cell immune response. While the clinical response to these therapies has been dramatic for some, many others have shown partial or even no response highlighting the need for alternative or synergistic approaches that activate innate immunity. Disruption of the interaction between SIRP alpha and CD47, an innate checkpoint inhibitor, using anti-CD47 antibodies, for example, is known to enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages and dendritic cells (DCs) leading to processing and presentation of tumor antigens. Recently, we described AO-176, a next generation anti-CD47 antibody that blocks the CD47/SIRP alpha interaction, induces phagocytosis and causes a direct tumor cell-autonomous death while negligibly binding RBCs. Herein, we characterize the ability of our CD47 antibodies such as AO-176 to induce immunogenic cell death (ICD) and damage-associated molecular patterns (DAMPs) in tumor cells and to potentiate chemotherapy-induced ICD/DAMPs. ICD is a process whereby an agent induces cell surface exposure and release of DAMPs from dying cells which stimulates DCs and adaptive immune responses. Tumor cells were treated in vitro with our CD47 antibodies either alone or in combination with chemotherapeutics followed by assessment of ICD/DAMPs using flow cytometry and biochemical assays. RNAseq was also performed on cells undergoing CD47 antibody mediated ICD/DAMP induction to better understand how CD47 inhibition may regulate ICD. AO-176 and other CD47 antibodies, developed by Arch Oncology, caused mitochondrial stress and loss of outer-membrane integrity, typically observed prior to cells undergoing apoptosis. In addition, CD47 antibody treatment induced a significant ER stress response at the genetic level resulting in the surface exposure of ER chaperone proteins calreticulin, Hsp90, and PDIA3. Concomitantly, our CD47 antibodies increased autophagy and JAK/STAT signaling, which resulted in both ATP and HMGB1 release, respectively. Finally, we demonstrated that in combination, our antibodies potentiated the effects of ICD/DAMP-inducing chemotherapy (e.g., doxorubicin). Here, we describe the unique ability of a specific subset of next generation CD47 antibodies, such as AO-176 to induce ICD/DAMPs. RNAseq analysis of treated cells also revealed alteration of several pathways, including those where DAMPs play a role. In summary, next-generation CD47 antibodies such as AO-176 may provide a novel approach to enhancing the current landscape of checkpoint immunotherapy by enhancing both the innate and adaptive immune responses against tumors. Citation Format: Daniel S. Pereira, Benjamin J. Capoccia, Ronald R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. Casey Wilson, Pamela T. Manning, Robert W. Carr. AO-176, a next-generation anti-CD47 antibody, i
最近在癌症免疫治疗方面取得的成功是针对PD-1、PDL-1和CTLA-4等免疫检查点来增强适应性t细胞免疫反应的细胞毒性活性。虽然对这些疗法的临床反应对一些人来说是戏剧性的，但许多其他人表现出部分反应甚至没有反应，这突出了激活先天免疫的替代或协同方法的必要性。例如，使用抗CD47抗体破坏SIRP α和CD47(一种先天检查点抑制剂)之间的相互作用，已知可以通过增加巨噬细胞和树突状细胞(DCs)对肿瘤细胞的吞噬作用，从而增强先天免疫，从而导致肿瘤抗原的加工和呈递。最近，我们描述了AO-176，一种新一代抗CD47抗体，它阻断CD47/SIRP α相互作用，诱导吞噬并导致肿瘤细胞直接自主死亡，而与红细胞的结合可以忽略不计。在此，我们描述了我们的CD47抗体如AO-176在肿瘤细胞中诱导免疫原性细胞死亡(ICD)和损伤相关分子模式(DAMPs)的能力，并增强了化疗诱导的ICD/DAMPs。ICD是一种药物诱导细胞表面暴露并从死亡细胞释放DAMPs的过程，从而刺激dc和适应性免疫反应。在体外用我们的CD47抗体单独或联合化疗药物治疗肿瘤细胞，然后用流式细胞术和生化分析评估ICD/DAMPs。RNAseq也在CD47抗体介导的ICD/DAMP诱导的细胞上进行，以更好地了解CD47抑制如何调节ICD。由Arch Oncology开发的AO-176和其他CD47抗体引起线粒体应激和外膜完整性丧失，通常在细胞凋亡前观察到。此外，CD47抗体处理在遗传水平上诱导了显著的内质网应激反应，导致内质网伴侣蛋白calreticulin、Hsp90和PDIA3表面暴露。同时，我们的CD47抗体增加了自噬和JAK/STAT信号，分别导致ATP和HMGB1的释放。最后，我们证明了联合使用，我们的抗体增强了ICD/ damp诱导化疗的作用(例如，阿霉素)。在这里，我们描述了下一代CD47抗体的一个特定子集，如AO-176诱导ICD/DAMPs的独特能力。处理细胞的RNAseq分析也揭示了几种途径的改变，包括DAMPs发挥作用的途径。总之，下一代CD47抗体如AO-176可能通过增强针对肿瘤的先天和适应性免疫反应，为增强检查点免疫治疗的现状提供一种新的途径。引文格式:Daniel S. Pereira, Benjamin J. Capoccia, Ronald R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. Casey Wilson, Pamela T. Manning, Robert W. Carr新一代抗cd47抗体AO-176诱导免疫原性细胞死亡[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A147。
{"title":"Abstract A147: AO-176, a next-generation anti-CD47 antibody, induces immunogenic cell death","authors":"D. Pereira, Benjamin J. Capoccia, R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. C. Wilson, P. Manning, R. Carr","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A147","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A147","url":null,"abstract":"Recent success in cancer immunotherapy has targeted immune checkpoints such as PD-1, PDL-1, and CTLA-4 to enhance the cytotoxic activity of the adaptive T-cell immune response. While the clinical response to these therapies has been dramatic for some, many others have shown partial or even no response highlighting the need for alternative or synergistic approaches that activate innate immunity. Disruption of the interaction between SIRP alpha and CD47, an innate checkpoint inhibitor, using anti-CD47 antibodies, for example, is known to enhance innate immunity by increasing the phagocytosis of tumor cells by macrophages and dendritic cells (DCs) leading to processing and presentation of tumor antigens. Recently, we described AO-176, a next generation anti-CD47 antibody that blocks the CD47/SIRP alpha interaction, induces phagocytosis and causes a direct tumor cell-autonomous death while negligibly binding RBCs. Herein, we characterize the ability of our CD47 antibodies such as AO-176 to induce immunogenic cell death (ICD) and damage-associated molecular patterns (DAMPs) in tumor cells and to potentiate chemotherapy-induced ICD/DAMPs. ICD is a process whereby an agent induces cell surface exposure and release of DAMPs from dying cells which stimulates DCs and adaptive immune responses. Tumor cells were treated in vitro with our CD47 antibodies either alone or in combination with chemotherapeutics followed by assessment of ICD/DAMPs using flow cytometry and biochemical assays. RNAseq was also performed on cells undergoing CD47 antibody mediated ICD/DAMP induction to better understand how CD47 inhibition may regulate ICD. AO-176 and other CD47 antibodies, developed by Arch Oncology, caused mitochondrial stress and loss of outer-membrane integrity, typically observed prior to cells undergoing apoptosis. In addition, CD47 antibody treatment induced a significant ER stress response at the genetic level resulting in the surface exposure of ER chaperone proteins calreticulin, Hsp90, and PDIA3. Concomitantly, our CD47 antibodies increased autophagy and JAK/STAT signaling, which resulted in both ATP and HMGB1 release, respectively. Finally, we demonstrated that in combination, our antibodies potentiated the effects of ICD/DAMP-inducing chemotherapy (e.g., doxorubicin). Here, we describe the unique ability of a specific subset of next generation CD47 antibodies, such as AO-176 to induce ICD/DAMPs. RNAseq analysis of treated cells also revealed alteration of several pathways, including those where DAMPs play a role. In summary, next-generation CD47 antibodies such as AO-176 may provide a novel approach to enhancing the current landscape of checkpoint immunotherapy by enhancing both the innate and adaptive immune responses against tumors. Citation Format: Daniel S. Pereira, Benjamin J. Capoccia, Ronald R. Hiebsch, Michael J. Donio, Alun J. Carter, Robyn J. Puro, W. Casey Wilson, Pamela T. Manning, Robert W. Carr. AO-176, a next-generation anti-CD47 antibody, i","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78982856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A153
T. Sen, B. L. Rodriguez, Limo Chen, N. Morikawa, J. Fujimoto, L. Diao, Youhong Fan, Jing Wang, B. Glisson, I. Wistuba, J. Sage, J. Heymach, D. Gibbons, L. Byers
Purpose of the Study: Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB) with programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies as monotherapy or combination. Therefore, there is a critical need to develop strategies to enhance the efficacy of ICB in SCLC, an otherwise immunosuppressed disease with dismal 5-year survival rate of 30 years. We have previously shown that prexasertib and olaparib treatment enhanced the protein (but not mRNA) and surface expression of PD-L1 in SCLC cell lines and tumor models. Here we elucidate the previously unexplored mechanism of how DNA damage response targeting enhances antitumor immunity in SCLC. Methods: SCLC cell lines and immune competent murine models were treated with inhibitors targeting DNA damage repair (DDR) proteins, checkpoint kinase 1 (CHK1) (by prexasertib), poly (ADP-ribose) polymerase (PARP) (by olaparib) either as single agents or in combination with anti-PD-L1. End point analyses were done by Western blot, real-time RT-PCR, multicolor flow cytometry and reverse phase protein array (RPPA). Result: We observed increased PD-L1 glycosylation post-prexasertib and olaparib treatment. Prexasertib and/or olaparib +/- anti-PD-L1 combination activates mTOR and inactivates GSK3β pathway thus providing mechanistic insight into DDR-targeting mediated PD-L1 glycosylation and stabilization. We treated tumor-bearing immune-competent B6129F1 mice with either IgG (control), prexasertib (10mg/kg, 2/7), anti-PD-L1 (300ug, 1/7) or combination (n=10/group). At Day 21, anti-PD-L1 did not cause tumor regression and prexasertib treatment delayed tumor growth [T/C=0.31(p Citation Format: Triparna Sen, Bertha Leticia Rodriguez, Limo Chen, Naoto Morikawa, Junya Fujimoto, Lixia Diao, Youhong Fan, Jing Wang, Bonnie S. Glisson, Ignasio Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons, Lauren A. Byers. Targeting DNA damage response upregulates PD-L1 level and promotes antitumor immunity in small-cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A153.
研究目的:尽管最近免疫疗法的使用取得了进展，但只有少数小细胞肺癌(SCLC)患者使用程序性细胞死亡蛋白1 (PD-1)或程序性死亡配体1 (PD-L1)抗体作为单药或联合治疗对免疫检查点阻断(ICB)有反应。因此，迫切需要制定策略来提高ICB在SCLC中的疗效，SCLC是一种免疫抑制疾病，5年生存率为30年。我们之前的研究表明，prexasertib和olaparib治疗增强了SCLC细胞系和肿瘤模型中PD-L1的蛋白(但不是mRNA)和表面表达。在这里，我们阐明了先前未被探索的DNA损伤反应靶向如何增强SCLC的抗肿瘤免疫的机制。方法:用靶向DNA损伤修复(DDR)蛋白、检查点激酶1 (CHK1) (prexasertib)、聚adp核糖聚合酶(PARP)(奥拉帕尼)的抑制剂单独或与抗pd - l1联合治疗SCLC细胞系和免疫能力强的小鼠模型。终点分析采用Western blot、实时RT-PCR、多色流式细胞术和反相蛋白阵列(RPPA)。结果:我们观察到普雷塞替和奥拉帕尼治疗后PD-L1糖基化升高。Prexasertib和/或olaparib +/-抗PD-L1联合激活mTOR并灭活GSK3β通路，从而为ddr靶向介导的PD-L1糖基化和稳定提供了机制见解。我们用IgG(对照组)、prexasertib (10mg/kg, 2/7)、抗pd - l1 (300ug, 1/7)或联合用药(n=10/组)治疗荷瘤免疫能力B6129F1小鼠。在第21天，抗pd - l1未引起肿瘤消退，而prexertib治疗延迟肿瘤生长[T/C=0.31(p)]。引用形式:Triparna Sen, Bertha Leticia Rodriguez, Limo Chen, Naoto Morikawa, Junya Fujimoto, Lixia Diao, Youhong Fan, Jing Wang, Bonnie S. Glisson, Ignasio Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons, Lauren A. Byers。靶向DNA损伤反应上调PD-L1水平，促进小细胞肺癌的抗肿瘤免疫[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫，2019;7(2增刊):摘要nr A153。
{"title":"Abstract A153: Targeting DNA damage response upregulates PD-L1 level and promotes antitumor immunity in small-cell lung cancer","authors":"T. Sen, B. L. Rodriguez, Limo Chen, N. Morikawa, J. Fujimoto, L. Diao, Youhong Fan, Jing Wang, B. Glisson, I. Wistuba, J. Sage, J. Heymach, D. Gibbons, L. Byers","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A153","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A153","url":null,"abstract":"Purpose of the Study: Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB) with programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies as monotherapy or combination. Therefore, there is a critical need to develop strategies to enhance the efficacy of ICB in SCLC, an otherwise immunosuppressed disease with dismal 5-year survival rate of 30 years. We have previously shown that prexasertib and olaparib treatment enhanced the protein (but not mRNA) and surface expression of PD-L1 in SCLC cell lines and tumor models. Here we elucidate the previously unexplored mechanism of how DNA damage response targeting enhances antitumor immunity in SCLC. Methods: SCLC cell lines and immune competent murine models were treated with inhibitors targeting DNA damage repair (DDR) proteins, checkpoint kinase 1 (CHK1) (by prexasertib), poly (ADP-ribose) polymerase (PARP) (by olaparib) either as single agents or in combination with anti-PD-L1. End point analyses were done by Western blot, real-time RT-PCR, multicolor flow cytometry and reverse phase protein array (RPPA). Result: We observed increased PD-L1 glycosylation post-prexasertib and olaparib treatment. Prexasertib and/or olaparib +/- anti-PD-L1 combination activates mTOR and inactivates GSK3β pathway thus providing mechanistic insight into DDR-targeting mediated PD-L1 glycosylation and stabilization. We treated tumor-bearing immune-competent B6129F1 mice with either IgG (control), prexasertib (10mg/kg, 2/7), anti-PD-L1 (300ug, 1/7) or combination (n=10/group). At Day 21, anti-PD-L1 did not cause tumor regression and prexasertib treatment delayed tumor growth [T/C=0.31(p Citation Format: Triparna Sen, Bertha Leticia Rodriguez, Limo Chen, Naoto Morikawa, Junya Fujimoto, Lixia Diao, Youhong Fan, Jing Wang, Bonnie S. Glisson, Ignasio Wistuba, Julien Sage, John V. Heymach, Don L. Gibbons, Lauren A. Byers. Targeting DNA damage response upregulates PD-L1 level and promotes antitumor immunity in small-cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A153.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80817722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A143
Meike E. W. Logtenberg
Cancer cells are able to evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. CD47 serves as a “don9t eat me” signal for myeloid cells by binding to the inhibitory receptor signal-regulatory protein alpha (SIRPα). Prior work has provided strong evidence that antibody-based targeting of the CD47 axis can promote tumor control by both innate and adaptive immune cells, and clinical development of CD47 antagonists is ongoing. Using a haploid genetic screen, we identify glutaminyl-peptide cyclotransferase-like (QPCTL) as a regulator of the CD47-SIRPα checkpoint that is critical for pyroglutamate formation on CD47 at the SIRPα binding site. Both genetic and pharmacologic interference with QPCTL activity decrease SIRPα binding to CD47 and enhances antibody-dependenT-cellular phagocytosis and cellular cytotoxicity of tumor cells mediated by macrophages and neutrophils, respectively. Furthermore, interference with QPCTL expression leads to a major increase in tumor cell killing and neutrophil influx by tumor-opsonizing antibodies in vivo. These data provide an avenue for small-molecule inhibition of the CD47 pathway to augment antibody therapy of cancer. Citation Format: Meike Emma Willemijn Logtenberg. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A143.
癌细胞能够通过在免疫效应细胞上结合其同源受体的抑制配体的表达来逃避免疫监视。CD47通过与抑制受体信号调节蛋白α (SIRPα)结合，为髓细胞提供“不要吃我”的信号。先前的研究已经提供了强有力的证据，证明基于抗体靶向CD47轴可以促进先天免疫细胞和适应性免疫细胞对肿瘤的控制，CD47拮抗剂的临床开发正在进行中。利用单倍体遗传筛选，我们鉴定出谷氨酰胺肽环转移酶样(QPCTL)是CD47-SIRPα检查点的调节剂，该检查点对于SIRPα结合位点CD47上焦谷氨酸的形成至关重要。遗传和药理学干扰QPCTL活性可降低SIRPα与CD47的结合，增强巨噬细胞和中性粒细胞介导的肿瘤细胞的抗体依赖性吞噬和细胞毒性。此外，对QPCTL表达的干扰导致肿瘤细胞杀伤和中性粒细胞内流在体内被肿瘤调节抗体显著增加。这些数据为CD47途径的小分子抑制提供了一条途径，以增强癌症的抗体治疗。引用格式:Meike Emma Willemijn Logtenberg。谷氨酰环化酶是CD47- SIRPα轴的酶修饰剂，也是免疫治疗的靶标[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫，2019;7(2增刊):摘要nr A143。
{"title":"Abstract A143: Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy","authors":"Meike E. W. Logtenberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A143","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A143","url":null,"abstract":"Cancer cells are able to evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. CD47 serves as a “don9t eat me” signal for myeloid cells by binding to the inhibitory receptor signal-regulatory protein alpha (SIRPα). Prior work has provided strong evidence that antibody-based targeting of the CD47 axis can promote tumor control by both innate and adaptive immune cells, and clinical development of CD47 antagonists is ongoing. Using a haploid genetic screen, we identify glutaminyl-peptide cyclotransferase-like (QPCTL) as a regulator of the CD47-SIRPα checkpoint that is critical for pyroglutamate formation on CD47 at the SIRPα binding site. Both genetic and pharmacologic interference with QPCTL activity decrease SIRPα binding to CD47 and enhances antibody-dependenT-cellular phagocytosis and cellular cytotoxicity of tumor cells mediated by macrophages and neutrophils, respectively. Furthermore, interference with QPCTL expression leads to a major increase in tumor cell killing and neutrophil influx by tumor-opsonizing antibodies in vivo. These data provide an avenue for small-molecule inhibition of the CD47 pathway to augment antibody therapy of cancer. Citation Format: Meike Emma Willemijn Logtenberg. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and target for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A143.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"5 Suppl 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82297324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A128
A. Dimberg, Alexandros Karampatzakis, S. Tuit, Mohanraj Ramachandran, G. Fotaki, L. Hooren, Hua Huang, R. Lugano, Kaunisto Aura, P. Ellmark, S. Mangsbo, J. Schultze, M. Essand, Maria Georganaki
CD40, a tumor necrosis factor receptor superfamily member, is a promising immune-boosting target in cancer immunotherapy due to its role in promoting antitumor responses of immune cells. CD40 is also expressed on endothelial cells but the response of the tumor-associated vasculature to CD40-stimulating immunotherapy has not been studied. Herein, we have performed RNA-sequencing analysis of murine tumor endothelial cells (TECs) isolated from B16.F10 melanoma and MB49 bladder cancer treated with agonistic CD40 monoclonal antibody (mAb) or isotype control. Gene set and gene ontology enrichment analyses of the differentially expressed genes revealed that CD40 mAb treatment induces interferon-γ (IFNγ) signaling in the tumor microenvironment associated with up-regulation of immunosuppressive genes in TECs, including the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1). Importantly, IDO1 was preferentially expressed in endothelial cells in the tumor and was positively correlated to infiltration of T-cells in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Collectively, our data suggest that IDO1 up-regulation in TECs occurs as a response to T-cell activation. Combining CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival of B16.F10 tumor-bearing mice, which was associated with increased activation of cytotoxic T-cells. Hereby, we have uncovered a novel immunosuppressive feedback mechanism, in which the tumor vasculature limits the response to cancer immunotherapy by up-regulating IDO1. Citation Format: Anna Dimberg, Alexandros Karampatzakis, Sander Tuit, Mohanraj Ramachandran, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Kaunisto Aura, Peter Ellmark, Sara M Mangsbo, Joachim L. Schultze, Magnus Essand, Maria Georganaki. Tumor endothelial cells say IDO to CD40-stimulating immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A128.
CD40是肿瘤坏死因子受体超家族成员，由于其促进免疫细胞抗肿瘤反应的作用，在癌症免疫治疗中是一个很有前途的免疫增强靶点。CD40也在内皮细胞上表达，但肿瘤相关血管对CD40刺激免疫疗法的反应尚未研究。在此，我们对B16分离的小鼠肿瘤内皮细胞(TECs)进行了rna测序分析。用激动性CD40单克隆抗体(mAb)或同型对照治疗F10黑色素瘤和MB49膀胱癌。差异表达基因的基因集和基因本体富集分析显示，CD40单抗治疗诱导肿瘤微环境中的干扰素-γ (IFNγ)信号通路，与tec中免疫抑制基因上调有关，包括吲哚胺2,3 -双加氧酶1 (IDO1)。重要的是，IDO1在肿瘤内皮细胞中优先表达，并与肿瘤微环境中t细胞的浸润呈正相关。在体外，内皮细胞响应t细胞来源的IFNγ上调IDO1，但不响应cd40刺激。总的来说，我们的数据表明，TECs中的IDO1上调是对t细胞激活的反应。CD40单抗与IDO1抑制剂epacadostat联合治疗可延缓肿瘤生长并提高B16的生存率。F10荷瘤小鼠，这与细胞毒性t细胞活化增加有关。因此，我们发现了一种新的免疫抑制反馈机制，其中肿瘤血管通过上调IDO1来限制对癌症免疫治疗的反应。引文格式:Anna Dimberg, Alexandros Karampatzakis, Sander Tuit, Mohanraj Ramachandran, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Kaunisto Aura, Peter Ellmark, Sara M Mangsbo, Joachim L. Schultze, Magnus Essand, Maria Georganaki。肿瘤内皮细胞对刺激cd40的免疫治疗产生IDO反应[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约，纽约。费城(PA): AACR;癌症免疫，2019;7(2增刊):摘要nr A128。
{"title":"Abstract A128: Tumor endothelial cells say IDO to CD40-stimulating immunotherapy","authors":"A. Dimberg, Alexandros Karampatzakis, S. Tuit, Mohanraj Ramachandran, G. Fotaki, L. Hooren, Hua Huang, R. Lugano, Kaunisto Aura, P. Ellmark, S. Mangsbo, J. Schultze, M. Essand, Maria Georganaki","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A128","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A128","url":null,"abstract":"CD40, a tumor necrosis factor receptor superfamily member, is a promising immune-boosting target in cancer immunotherapy due to its role in promoting antitumor responses of immune cells. CD40 is also expressed on endothelial cells but the response of the tumor-associated vasculature to CD40-stimulating immunotherapy has not been studied. Herein, we have performed RNA-sequencing analysis of murine tumor endothelial cells (TECs) isolated from B16.F10 melanoma and MB49 bladder cancer treated with agonistic CD40 monoclonal antibody (mAb) or isotype control. Gene set and gene ontology enrichment analyses of the differentially expressed genes revealed that CD40 mAb treatment induces interferon-γ (IFNγ) signaling in the tumor microenvironment associated with up-regulation of immunosuppressive genes in TECs, including the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1). Importantly, IDO1 was preferentially expressed in endothelial cells in the tumor and was positively correlated to infiltration of T-cells in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Collectively, our data suggest that IDO1 up-regulation in TECs occurs as a response to T-cell activation. Combining CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival of B16.F10 tumor-bearing mice, which was associated with increased activation of cytotoxic T-cells. Hereby, we have uncovered a novel immunosuppressive feedback mechanism, in which the tumor vasculature limits the response to cancer immunotherapy by up-regulating IDO1. Citation Format: Anna Dimberg, Alexandros Karampatzakis, Sander Tuit, Mohanraj Ramachandran, Grammatiki Fotaki, Luuk van Hooren, Hua Huang, Roberta Lugano, Kaunisto Aura, Peter Ellmark, Sara M Mangsbo, Joachim L. Schultze, Magnus Essand, Maria Georganaki. Tumor endothelial cells say IDO to CD40-stimulating immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A128.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80618071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A150
M. Rybstein, T. Yamazaki, Aitziber Buqué Martinez, L. Galluzzi
Background: Macroautophagy (autophagy) is an evolutionary conserved cellular mechanism culminating with the lysosomal degradation of dispensable, damaged or potentially toxic cytoplasmic structures (e.g., permeabilized mitochondria). Autophagy helps cancer cells to adapt to harsh environmental conditions and to resist therapy. However, autophagy is also key for multiple steps of the anticancer immune response. Thus, whether autophagy should be inhibited or activated in the context of cancer therapy remains debated (Rybstein et al., Nat Cell Biol 2018). Since autophagy has been shown to play a key role in removal of cytosolic DNA, which is one mechanism leading to type I interferon (IFN) secretion, and since type I IFN is required for systemic immune responses activated by radiation therapy (RT), we asked the question as to whether selectively inhibiting autophagy in cancer cells may boost the ability of RT to initiate anticancer immunity. Methods/Tools: CRISPR/Cas9 technology was used to render mouse mammary carcinoma TSA and EO771 cells autophagy-deficient and chemical inhibitors of autophagy were also employed. Autophagy-competent versus –deficient systems were characterized for autophagy proficiency (by immunoblotting), growth (in vitro and in vivo), resistance to cell death induced by starvation, chemotherapy and RT (by multicolor flow cytometry and clonogenic assays) and production of type I IFN (by PCR and ELISA). Abscopal responses have been assessed in vivo. Results: In line with previous observations, autophagy inhibition reduced the growth of mouse mammary carcinoma cells, in vitro and in vivo, limited their clonogenic potential (at baseline) and increased their sensitivity to multiple stressors. Moreover, pharmacologic and genetic autophagy inhibition increased the capacity of mouse mammary carcinoma cells to secrete type I IFN in response to radiation. Finally, immunocompetent mice bearing syngeneic autophagy-deficient mouse mammary carcinoma cells mounted improved abscopal responses to RT (in the context of CTLA4 blockade) as compared to immunocompetent mice bearing syngeneic autophagy-competent cells, as determined by growth inhibition of a distant, non-irradiated, autophagy-competent lesion. Perspectives: We will test the innovative hypothesis that selective autophagy inhibition in cancer cells may synergize with autophagy activation at the whole-body level (by nutrient restriction or physical exercise), hence enabling superior therapeutic responses to radiation. Citation Format: Marissa Rybstein, Takahiro Yamazaki, Aitziber Buque Martinez, Lorenzo Galluzzi. Enhancing abscopal responses to radiation therapy by manipulating autophagy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A150.
{"title":"Abstract A150: Enhancing abscopal responses to radiation therapy by manipulating autophagy","authors":"M. Rybstein, T. Yamazaki, Aitziber Buqué Martinez, L. Galluzzi","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A150","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A150","url":null,"abstract":"Background: Macroautophagy (autophagy) is an evolutionary conserved cellular mechanism culminating with the lysosomal degradation of dispensable, damaged or potentially toxic cytoplasmic structures (e.g., permeabilized mitochondria). Autophagy helps cancer cells to adapt to harsh environmental conditions and to resist therapy. However, autophagy is also key for multiple steps of the anticancer immune response. Thus, whether autophagy should be inhibited or activated in the context of cancer therapy remains debated (Rybstein et al., Nat Cell Biol 2018). Since autophagy has been shown to play a key role in removal of cytosolic DNA, which is one mechanism leading to type I interferon (IFN) secretion, and since type I IFN is required for systemic immune responses activated by radiation therapy (RT), we asked the question as to whether selectively inhibiting autophagy in cancer cells may boost the ability of RT to initiate anticancer immunity. Methods/Tools: CRISPR/Cas9 technology was used to render mouse mammary carcinoma TSA and EO771 cells autophagy-deficient and chemical inhibitors of autophagy were also employed. Autophagy-competent versus –deficient systems were characterized for autophagy proficiency (by immunoblotting), growth (in vitro and in vivo), resistance to cell death induced by starvation, chemotherapy and RT (by multicolor flow cytometry and clonogenic assays) and production of type I IFN (by PCR and ELISA). Abscopal responses have been assessed in vivo. Results: In line with previous observations, autophagy inhibition reduced the growth of mouse mammary carcinoma cells, in vitro and in vivo, limited their clonogenic potential (at baseline) and increased their sensitivity to multiple stressors. Moreover, pharmacologic and genetic autophagy inhibition increased the capacity of mouse mammary carcinoma cells to secrete type I IFN in response to radiation. Finally, immunocompetent mice bearing syngeneic autophagy-deficient mouse mammary carcinoma cells mounted improved abscopal responses to RT (in the context of CTLA4 blockade) as compared to immunocompetent mice bearing syngeneic autophagy-competent cells, as determined by growth inhibition of a distant, non-irradiated, autophagy-competent lesion. Perspectives: We will test the innovative hypothesis that selective autophagy inhibition in cancer cells may synergize with autophagy activation at the whole-body level (by nutrient restriction or physical exercise), hence enabling superior therapeutic responses to radiation. Citation Format: Marissa Rybstein, Takahiro Yamazaki, Aitziber Buque Martinez, Lorenzo Galluzzi. Enhancing abscopal responses to radiation therapy by manipulating autophagy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A150.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87627004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：