Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A149
S. Roth, Shienny Sampurno, M. Waibel, L. Cluse, L. Pereira, R. Johnstone, R. Ramsay
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer, predominantly in children but patients over 50 years are also affected. While high-intensity combination chemotherapy is effective in 90% of young patients, only 30–40% of adult patients with ALL will achieve long-term remission. Furthermore, the severe side effects observed in young and old patients highlight the need for alternative therapy options. To explore the role of drivers of ALL and thus the potential for other therapy options we crossed EµTEL-JAK2 mice, a mouse model of T-ALL, with MybPlt4/Plt4 mice, which express hypomorphic alleles of Myb resulting in 40% of WT Myb function. EµTEL-JAK2 x MybPlt4/Plt4 mice showed a significant prolonged survival compared to EµTEL-JAK2 Myb+/+ mice, indicating that EµTEL-JAK2 cells are dependent upon fully functional Myb. Hence, we initiated a preclinical study targeting Myb with our TetMyb DNA vaccine combined with immune checkpoint inhibitors in C57BL/6 mice bearing transplanted Eµ TEL-JAK2 T-ALL cells. Interestingly, therapeutic treatment with TetMyb DNA vaccine and anti-PD-1 antibody therapy did not enhance overall survival. However, therapeutic monotherapy with anti-CTLA-4 antibody therapy on day 2, 7, 12, 16 and 21 after EµTEL-JAK2 transplant significantly reduced leukemic cell frequency in the peripheral blood and significantly prolonged survival. Further evaluation, especially in combination with current standard of care, is needed, but our results suggest a promising therapeutic option of anti-CTLA-4 antibody therapy in T-ALL. Citation Format: Sara Roth, Shienny Sampurno, Michaela Waibel, Leonie Cluse, Lloyd A. Pereira, Ricky W. Johnstone, Robert G. Ramsay. EµTel-Jak2 T-ALL mouse model is dependent upon Myb function and susceptible to immune checkpoint therapy [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 A149.
t细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性血液学癌症，主要发生在儿童中，但50岁以上的患者也会受到影响。虽然高强度联合化疗对90%的年轻患者有效，但只有30-40%的成年ALL患者能获得长期缓解。此外，在年轻和老年患者中观察到的严重副作用突出了替代治疗方案的必要性。为了探索ALL驱动因素的作用，从而探索其他治疗方案的潜力，我们将T-ALL小鼠模型EµTEL-JAK2小鼠与MybPlt4/Plt4小鼠进行杂交，后者表达Myb的亚型等位基因，导致40%的WT Myb功能。与EµTEL-JAK2 Myb+/+小鼠相比，EµTEL-JAK2 x MybPlt4/Plt4小鼠的存活时间明显延长，这表明EµTEL-JAK2细胞依赖于完全功能的Myb。因此，我们在携带移植的EµTEL-JAK2 T-ALL细胞的C57BL/6小鼠中启动了一项针对Myb的临床前研究，该研究使用我们的TetMyb DNA疫苗联合免疫检查点抑制剂。有趣的是，TetMyb DNA疫苗和抗pd -1抗体治疗并没有提高总生存率。然而，在EµTEL-JAK2移植后第2、7、12、16和21天，单抗ctla -4抗体治疗可显著降低外周血白血病细胞频率，显著延长生存期。需要进一步的评估，特别是与目前的标准护理相结合，但我们的研究结果表明抗ctla -4抗体治疗T-ALL是一种有希望的治疗选择。引文格式:Sara Roth, Shienny Sampurno, Michaela Waibel, Leonie Cluse, Lloyd A. Pereira, Ricky W. Johnstone, Robert G. Ramsay。EµTel-Jak2 T-ALL小鼠模型依赖Myb功能，对免疫检查点治疗敏感[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 A149。
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Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A154
E. Shklovskaya, Jenny H. Lee, S. Lim, S. Alavi, J. Thompson, R. Saw, M. Carlino, R. Scolyer, A. Menzies, G. Long, R. Kefford, H. Rizos
Antibodies directed against the programmed cell death protein 1 (PD-1) immune checkpoint have significantly improved survival of patients with advanced metastatic melanoma. Innate and acquired resistance to anti-PD-1 treatment represents a significant treatment obstacle, yet the mechanisms of resistance are poorly understood and remain difficult to model at the cellular level. Here we used multiparameter flow cytometry to examine the immune profiles of 39 tumor biopsies obtained from 31 patients with stage III-IV metastatic melanoma prior to (baseline, n = 21) or during (n = 18) single-agent anti-PD1 immunotherapy; twelve patients developed resistance to treatment. Samples were enzymatically dissociated and cryopreserved until thawed and stained with fluorescently labeled antibodies to enable a comprehensive analysis of melanoma cells and tumor infiltrating lymphocytes (TILs). Mean melanoma cell content was 57+4.7% (mean+s.e.m.) while mean immune infiltrate (CD45 positive cells) was 31.5+4.5%. Analysis of melanoma cell expression of antigen presenting molecules and PD-1 ligands revealed frequent downregulation of HLA-ABC expression in both baseline (9/21, 43%) and on-treatment tumors (10/18, 56%), including a complete HLA-ABC loss in 2/39 samples. HLA-ABC up-regulation was observed in 9/39 (23%) tumors. Expression of HLA-DR and PD-L1 strongly correlated with that of HLA-ABC (Spearman r=0.68 and =0.89, respectively), indicative of local interferon exposure. Unlike PD-L1, melanoma cell expression of PD-L2 was low in the biopsied tissue. In contrast, PD-L2 expression was readily induced by gamma interferon and correlated with HLA-ABC expression in matching melanoma cell lines established from the dissociated biopsies (9/39). We found multiple correlations between parameters characterizing the immune profiles of tumor cells and TILs in both baseline and on-treatment samples. Among significant treatment-associated changes, conventional T-cells bearing the αβ T-cell receptor were 1.4-fold higher in the on-treatment group compared to baseline (65+2.7% versus 46.2+4.1%, P Citation Format: Elena Shklovskaya, Jenny Lee, Su Yin Lim, Sara Alavi, John Thompson, Robyn Saw, Matteo Carlino, Richard Scolyer, Alexander Menzies, Georgina Long, Richard Kefford, Helen Rizos. Flow cytometric analysis of immune responses in the melanoma tissue biopsies before or during anti-PD1 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 A154.
针对程序性细胞死亡蛋白1 (PD-1)免疫检查点的抗体显著提高了晚期转移性黑色素瘤患者的生存率。对抗pd -1治疗的先天和获得性耐药是一个重要的治疗障碍，但耐药机制尚不清楚，难以在细胞水平上建立模型。在这里，我们使用多参数流式细胞术检查了31例III-IV期转移性黑色素瘤患者在(基线，n = 21)或(n = 18)单药抗pd1免疫治疗之前或期间获得的39例肿瘤活检的免疫谱;12名患者对治疗产生了耐药性。样品被酶解并冷冻保存至解冻，并用荧光标记抗体染色，以便对黑色素瘤细胞和肿瘤浸润淋巴细胞(til)进行全面分析。平均黑色素瘤细胞含量为57+4.7%(平均+s.e.m)，平均免疫浸润(CD45阳性细胞)为31.5+4.5%。对黑色素瘤细胞抗原呈递分子和PD-1配体表达的分析显示，在基线(9/21,43%)和治疗后肿瘤(10/18,56%)中，HLA-ABC表达频繁下调，包括2/39样本中HLA-ABC完全丧失。在9/39(23%)的肿瘤中观察到HLA-ABC上调。HLA-DR和PD-L1的表达与HLA-ABC的表达密切相关(Spearman r分别为0.68和0.89)，提示局部干扰素暴露。与PD-L1不同，PD-L2在活检组织中的黑色素瘤细胞表达较低。相比之下，γ干扰素很容易诱导PD-L2表达，并与分离活检建立的匹配黑色素瘤细胞系中HLA-ABC表达相关(9/39)。我们发现在基线和治疗样本中表征肿瘤细胞免疫特征的参数和TILs之间存在多重相关性。在显著的治疗相关变化中，治疗组携带αβ t细胞受体的常规t细胞比基线高1.4倍(65+2.7% vs 46.2+4.1%)， P引用形式:Elena Shklovskaya, Jenny Lee, Su Yin Lim, Sara Alavi, John Thompson, Robyn Saw, Matteo Carlino, Richard Scolyer, Alexander Menzies, Georgina Long, Richard Kefford, Helen Rizos。流式细胞术分析抗pd1免疫治疗前后黑色素瘤组织活检的免疫反应[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 A154。
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Pub Date : 2019-02-01DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A130
Henna Hakanen, M. Hernberg, S. Mäkelä, B. Yadav, O. Brück, S. Juteau, L. Kohtamäki, Mette Ilander, S. Mustjoki, K. Anna
Anti-PD1 therapy has proven to be effective in various cancer types, but not all patients benefit from the therapy. Further, no comprehensive immunologic monitoring during anti-PD1 treatment has yet been published. In this study, we aimed to discover the effects of anti-PD1 therapy on the immune system, especially on NK and NKT-cells, which are less studied, but known to be involved in antitumor immune events. Peripheral blood samples from immuno-oncology (IO) naive metastatic melanoma patients (n=20) were obtained before the first infusion of pembrolizumab or nivolumab (D0), then 1 and 3 months after the initiation of treatment. From each time-point, complete blood counts (CBC) were obtained, and comprehensive immunophenotyping of NK, NKT, and T-cells was performed with multicolor flow cytometry. Moreover, 92 different serum cytokines were measured using the Olink inflammation panel. The protein levels are presented as arbitrary units of normalized protein expression, NPX, on Log2 scale. The CBC revealed that the proportion of lymphocytes (mean D0 30.6% vs. 3mo 24.9%, p=0.02), decreased during the treatment but no changes were observed in absolute numbers or in other leukocytes. Immunophenotyping of lymphocyte subpopulations revealed that the frequency of NKT brighT-cells was increased (D0 1.8% vs. 1mo 2.3%, p=0.01) and that cytotoxic NK CD56dim cells expressed more CD25 (D0 19.5% vs. 1mo 23.7%, p=0.02) and CD45RO (D0 14.7% vs. 1mo 21.1%, p=0.03) surface markers after 1 month of therapy. The cytokine assay indicated that during anti-PD1 treatment the levels of CXC family cytokines were increased in the serum; CXCL9 (D0 470 vs. 1mo 1070, p=0.0003, D0 470 vs. 3mo 1227, p=0.0007), CXCL11 (D0 49.8 vs. 1mo 81.8, p=0.005), CXCL10 (D0 1000 vs. 1mo 2078, p=0.0003). Also, an increase in IL-12B (D0 31.6 vs. 1mo 41.2, p=0.003, D0 31.6 vs. 3mo 32.4, p=0.04) and TNFRSF9 (D0 126.4 vs. 1mo 181.0, p=0.01, D0 126.4 vs. 3mo 149.0, p=0.04) levels was observed.To further examine these results, patients were categorized into two cohorts: responders (R, n=6, PFS=17.0 months) and patients with progressive disease (PD, n=9, PFS=5.0 months) in terms of the duration of progression-free survival (PFS) and decrease in tumor burden. 5 patients were excluded due to challenging clinical evaluation of response. When examining the differences between these cohorts, CBC indicated a significant decrease in the mean frequency of lymphocytes in PD (D0 26.9% vs. 3mo 19.2%, p=0.04), but not in the R cohort. The responders had also higher frequency of lymphocytes at 1- and 3-month time-points (R 34.5% vs. PD 25.4%, p=0.02, R 32.4% vs. PD 19.2%, p=0.01, respectively) and lower frequency of neutrophils before initiation and after 1 and 3 months of treatment (R 50.8% vs. PD 58.6%, p=0.04, R 45.3% vs. PD 59.4%, p=0.01, R 49.8% vs. PD 64.5%, p=0.04, respectively). The CBC absolute counts revealed that the responders had less neutrophils (R 2.8 109/L vs. PD 4.9 109/L, p=0.04) and monocytes
抗pd1治疗已被证明对各种癌症类型有效，但并非所有患者都能从治疗中受益。此外，抗pd1治疗期间的综合免疫监测尚未发表。在本研究中，我们旨在发现抗pd1治疗对免疫系统的影响，特别是对NK和nkt细胞的影响，这两种细胞研究较少，但已知它们参与抗肿瘤免疫事件。免疫肿瘤学(IO)初发转移性黑色素瘤患者(n=20)的外周血样本在首次输注派姆单抗或纳武单抗(D0)之前获得，然后在治疗开始后1和3个月获得。从每个时间点开始，获得全血细胞计数(CBC)，并使用多色流式细胞术进行NK、NKT和t细胞的综合免疫分型。此外，使用Olink炎症面板测量了92种不同的血清细胞因子。蛋白质水平在Log2标度上以归一化蛋白质表达的任意单位NPX表示。CBC显示，治疗期间淋巴细胞比例(平均0岁30.6%比3岁24.9%，p=0.02)下降，但绝对数量和其他白细胞未见变化。淋巴细胞亚群免疫表型分析显示，治疗1个月后，NKT亮细胞的频率增加(D0 1.8%比1mo 2.3%， p=0.01)，细胞毒性NK CD56dim细胞表达CD25 (D0 19.5%比1mo 23.7%， p=0.02)和CD45RO (D0 14.7%比1mo 21.1%， p=0.03)表面标志物。细胞因子检测显示，抗pd1治疗期间血清CXC家族细胞因子水平升高;CXCL9 (D0 470 vs. 1mo 1070, p=0.0003, D0 470 vs. 3mo 1227, p=0.0007)， CXCL11 (D0 49.8 vs. 1mo 81.8, p=0.005)， CXCL10 (D0 1000 vs. 1mo 2078, p=0.0003)。此外，IL-12B (D0 31.6 vs. 1mo 41.2, p=0.003, D0 31.6 vs. 3mo 32.4, p=0.04)和TNFRSF9 (D0 126.4 vs. 1mo 181.0, p=0.01, D0 126.4 vs. 3mo 149.0, p=0.04)水平升高。为了进一步检验这些结果，根据无进展生存期(PFS)和肿瘤负担减少的时间，将患者分为两组:反应者(R, n=6, PFS=17.0个月)和进展性疾病患者(PD, n=9, PFS=5.0个月)。5例患者因对疗效的临床评价具有挑战性而被排除。当检查这些队列之间的差异时，CBC显示PD中淋巴细胞的平均频率显著降低(D0 26.9% vs. 3mo 19.2%， p=0.04)，但在R队列中没有。缓解者在治疗1个月和3个月时淋巴细胞频率较高(R为34.5%，PD为25.4%，p=0.02, R为32.4%，PD为19.2%，p=0.01)，治疗开始前和治疗1个月和3个月后中性粒细胞频率较低(R为50.8%，PD为58.6%，p=0.04, R为45.3%，PD为59.4%，p=0.01, R为49.8%，PD为64.5%，p=0.04)。CBC绝对计数显示，与PD相比，治疗3个月后，应答者的中性粒细胞(r2.8 109/L vs. PD 4.9 109/L, p=0.04)和单核细胞(r0.4 109/L vs. PD 0.7 109/L, p=0.04)减少。免疫表型分析显示，缓解者在治疗前(R 10.1% vs. PD 3.5%， p=0.03)和治疗3个月后(R 15.7% vs. PD 3.7%， p=0.03)有更多的NKT暗淡细胞，NKT明亮频率增加仅在R组(R 2.5% vs. 1个月3.4%，p=0.04)，而在PD组中未观察到。细胞因子检测显示，治疗1个月后，R组CXCL9水平升高(D0 476.8 vs. 1mo 1480.2, p=0.01)， PD组CXCL9水平升高(D0 476.8 vs. 1mo 1480.2, p=0.01)， PD组CXCL9水平升高(D0 1480.2 vs. PD 639.3, p=0.01)。根据我们的初步结果，我们认为血液中nkt细胞的高频率与阳性治疗反应有关，除了t细胞外，NK和nkt细胞也可能在PD-1抑制诱导的抗肿瘤反应中发挥关键作用。因此，需要进一步研究抗pd1治疗对NK和nkt细胞的影响，以更好地了解它们在阳性治疗反应中的作用。引文格式:Henna H.E. Hakanen, Micaela Hernberg, Siru Makela, Bhagwan Yadav, Oscar Bruck, Susanna Juteau, Laura Kohtamaki, Mette Ilander, Satu Mustjoki, Kreutzman Anna。对PD1治疗有反应的转移性黑色素瘤患者外周血nkt细胞比例较高[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 A130。
{"title":"Abstract A130: Metastatic melanoma patients responding to PD1 therapy have higher proportion of peripheral blood NKT-cells","authors":"Henna Hakanen, M. Hernberg, S. Mäkelä, B. Yadav, O. Brück, S. Juteau, L. Kohtamäki, Mette Ilander, S. Mustjoki, K. Anna","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A130","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A130","url":null,"abstract":"Anti-PD1 therapy has proven to be effective in various cancer types, but not all patients benefit from the therapy. Further, no comprehensive immunologic monitoring during anti-PD1 treatment has yet been published. In this study, we aimed to discover the effects of anti-PD1 therapy on the immune system, especially on NK and NKT-cells, which are less studied, but known to be involved in antitumor immune events. Peripheral blood samples from immuno-oncology (IO) naive metastatic melanoma patients (n=20) were obtained before the first infusion of pembrolizumab or nivolumab (D0), then 1 and 3 months after the initiation of treatment. From each time-point, complete blood counts (CBC) were obtained, and comprehensive immunophenotyping of NK, NKT, and T-cells was performed with multicolor flow cytometry. Moreover, 92 different serum cytokines were measured using the Olink inflammation panel. The protein levels are presented as arbitrary units of normalized protein expression, NPX, on Log2 scale. The CBC revealed that the proportion of lymphocytes (mean D0 30.6% vs. 3mo 24.9%, p=0.02), decreased during the treatment but no changes were observed in absolute numbers or in other leukocytes. Immunophenotyping of lymphocyte subpopulations revealed that the frequency of NKT brighT-cells was increased (D0 1.8% vs. 1mo 2.3%, p=0.01) and that cytotoxic NK CD56dim cells expressed more CD25 (D0 19.5% vs. 1mo 23.7%, p=0.02) and CD45RO (D0 14.7% vs. 1mo 21.1%, p=0.03) surface markers after 1 month of therapy. The cytokine assay indicated that during anti-PD1 treatment the levels of CXC family cytokines were increased in the serum; CXCL9 (D0 470 vs. 1mo 1070, p=0.0003, D0 470 vs. 3mo 1227, p=0.0007), CXCL11 (D0 49.8 vs. 1mo 81.8, p=0.005), CXCL10 (D0 1000 vs. 1mo 2078, p=0.0003). Also, an increase in IL-12B (D0 31.6 vs. 1mo 41.2, p=0.003, D0 31.6 vs. 3mo 32.4, p=0.04) and TNFRSF9 (D0 126.4 vs. 1mo 181.0, p=0.01, D0 126.4 vs. 3mo 149.0, p=0.04) levels was observed.To further examine these results, patients were categorized into two cohorts: responders (R, n=6, PFS=17.0 months) and patients with progressive disease (PD, n=9, PFS=5.0 months) in terms of the duration of progression-free survival (PFS) and decrease in tumor burden. 5 patients were excluded due to challenging clinical evaluation of response. When examining the differences between these cohorts, CBC indicated a significant decrease in the mean frequency of lymphocytes in PD (D0 26.9% vs. 3mo 19.2%, p=0.04), but not in the R cohort. The responders had also higher frequency of lymphocytes at 1- and 3-month time-points (R 34.5% vs. PD 25.4%, p=0.02, R 32.4% vs. PD 19.2%, p=0.01, respectively) and lower frequency of neutrophils before initiation and after 1 and 3 months of treatment (R 50.8% vs. PD 58.6%, p=0.04, R 45.3% vs. PD 59.4%, p=0.01, R 49.8% vs. PD 64.5%, p=0.04, respectively). The CBC absolute counts revealed that the responders had less neutrophils (R 2.8 109/L vs. PD 4.9 109/L, p=0.04) and monocytes ","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77384130","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-A145
E. Mugarza, F. V. Maldegem, M. Sopena, M. M. Arcas, J. Downward
Cancer immunotherapies such as immune checkpoint blockade have yielded long-term durable responses in some patients. Nevertheless, the majority of cancer patients do not respond to such therapies, which constitutes a large unmet need in the clinic. Tumors develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. Lung cancer is a highly immunogenic tumor type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. KRAS is an oncogene mutated in a third of lung cancer patients and has been previously shown to trigger immunosuppressive actions by tumour cells. We aim to study the immunosuppressive effects of KRAS mutations in vitro and in clinically relevant mouse models of lung adenocarcinoma. We have generated a tumor cell autonomous KRAS- dependent gene expression profile using in vitro systems. We have set a particular focus on genes playing a role in tumor immune evasion, whose function we are aiming to elucidate using immunogenic in vivo models. We have developed a derivative of the transplantable KRAS mutant murine Lewis lung adenocarcinoma (LLC) cell line in which KRAS activity can be specifically blocked using a small-molecule inhibitor. We aim to unravel the immune infiltration of such tumors and elucidate the specific role of KRAS in shaping its microenvironment. By combining simplistic in vitro models to unravel mechanisms of action and more complex mouse models to prove their clinical relevance, we aim to increase immune visibility of KRAS-mutated lung tumors to make them more susceptible to immune and other therapies. Citation Format: Edurne Mugarza, Febe van Maldegem, Miriam Llorian Sopena, Miriam Molina Arcas, Julian Downward. Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC [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 A145.
{"title":"Abstract A145: Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC","authors":"E. Mugarza, F. V. Maldegem, M. Sopena, M. M. Arcas, J. Downward","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A145","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A145","url":null,"abstract":"Cancer immunotherapies such as immune checkpoint blockade have yielded long-term durable responses in some patients. Nevertheless, the majority of cancer patients do not respond to such therapies, which constitutes a large unmet need in the clinic. Tumors develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. Lung cancer is a highly immunogenic tumor type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. KRAS is an oncogene mutated in a third of lung cancer patients and has been previously shown to trigger immunosuppressive actions by tumour cells. We aim to study the immunosuppressive effects of KRAS mutations in vitro and in clinically relevant mouse models of lung adenocarcinoma. We have generated a tumor cell autonomous KRAS- dependent gene expression profile using in vitro systems. We have set a particular focus on genes playing a role in tumor immune evasion, whose function we are aiming to elucidate using immunogenic in vivo models. We have developed a derivative of the transplantable KRAS mutant murine Lewis lung adenocarcinoma (LLC) cell line in which KRAS activity can be specifically blocked using a small-molecule inhibitor. We aim to unravel the immune infiltration of such tumors and elucidate the specific role of KRAS in shaping its microenvironment. By combining simplistic in vitro models to unravel mechanisms of action and more complex mouse models to prove their clinical relevance, we aim to increase immune visibility of KRAS-mutated lung tumors to make them more susceptible to immune and other therapies. Citation Format: Edurne Mugarza, Febe van Maldegem, Miriam Llorian Sopena, Miriam Molina Arcas, Julian Downward. Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC [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 A145.","PeriodicalId":18169,"journal":{"name":"Maintenance of Immune Balance: Effects of Targeted and Immune Therapies","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89266715","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}
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