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{"title":"Abstract B196: Examining proteasome sensitivity of lymphoid malignancy: Ubiquilin 1 (Ubqln1) is required for BCR-induced proliferation of B cells","authors":"Alexandra M. Whiteley, E. Brown, D. Finley","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B196","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B196","url":null,"abstract":"Careful regulation of protein levels is essential to cellular life, and the ubiquitin proteasome system is a major way in which cells coordinate the degradation of proteins. In addition to regulating steady state protein degradation, the ubiquitin proteasome system assists in major proteome reorganizations, including the response to cellular stresses and the completion of major milestones such as differentiation, stimulation, and cell division. Lymphocytes are a useful model with which to understand the regulation of protein degradation because they undergo dramatic proteome reorganization upon receptor:ligand interactions, and because some lymphocytic malignancies are uniquely sensitive to treatment with proteasome inhibitors. We have previously shown that B lymphocytes require Ubiquilin 1 (Ubqln1), an extrinsic proteasome receptor, for their proliferation downstream of BCR stimulation. Ubqlns help to facilitate the degradation of ubiquitinated protein by simultaneously binding the cap of the proteasome and ubiquitinated client proteins, but until recently the clients of Ubqln1, as well as the consequences of Ubqln1 loss, were unknown. The lack of Ubqln1 resulted in accumulation of mislocalized mitochondrial proteins and induced a block in protein synthesis downstream of BCR stimulation, which resulted in cell cycle inhibition. This work implicated a role for Ubqln1 both in immune activation as well as B cell malignancy. Unexpectedly, TLR stimulation was normal in Ubqln1-deficienT-cells. Two major hypotheses for this specificity involve unique signal transduction pathway activation, and overexpression of mitochondrial proteins downstream of BCR activation. In fact, dysregulation of BCR signal transduction cascades and upregulation of OXPHOS genes define common and partially overlapping subtypes of diffuse large B-cell lymphoma (DLBCL). Currently, we aim to resolve these hypotheses with both in vivo and in vitro approaches. These studies will sharpen our understanding of B-cell cancer susceptibility to perturbation of the ubiquitin proteasome system and of Ubqln1 function. Citation Format: Alexandra M. Whiteley, Eric Brown, Daniel Finley. Examining proteasome sensitivity of lymphoid malignancy: Ubiquilin 1 (Ubqln1) is required for BCR-induced proliferation of B cells [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 B196.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"86 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134555132","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}

{"title":"Abstract B182: Repurposing antiviral T-cells to fight tumors","authors":"Pamela C. Rosato, Sathi Wijeyesinghe, J. Stolley, Christine E. Nelson, Rachel L. Davis, Luke S Manlove, C. Pennell, B. Blazar, Clark C. Chen, M. Geller, V. Vezys, D. Masopust","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B182","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B182","url":null,"abstract":"Overcoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpoint blockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. Humans experience many viral infections. Once controlled, the host retains memory T-cells throughout the entire body to sense reinfection or recrudescence. Mouse models have demonstrated that when that same virus is reencountered, these T-cells sound an alarm that induces a local immunostimulatory environment that activates and recruits many arms of the immune system. We observed that, like healthy tissue, human tumors are commonly surveyed by memory T-cells specific for previously encountered viral infections. Antiviral T-cell immune surveillance of tumors was recapitulated in mouse cancer models. We tested and discovered that local delivery of adjuvant-free peptide, derived from previously encountered mouse viral infections, recapitulated the sensing and alarm T-cell function within the tumor: recruiting and activating both the innate and adaptive immune system. This approach induced intratumoral accumulation of granzyme B+ CD8+ T and NK cells, and activated dendritic cells within the tumor and subsequently within the tumor draining lymph node. In addition to stimulating the tumor microenvironment, preliminary data suggest activated antiviral T-cells directly killed peptide coated tumor cells. Viral peptide administration arrested rapidly growing and poorly immunogenic B16 melanomas in vivo and this treatment synergized with anti-PD-L1 checkpoint blockade to eliminate measurable tumors, and prevented recurrence in 34% of mice. Most cured mice rejected subsequent B16 tumor challenges at distant sites, indicating that effective systemic tumor-specific immunity was established. In support of the hypothesis that this approach could translate to human cancer immunotherapy, we found that viral peptide alarm therapy of freshly isolated human tumors drove similar immune activation to that observed in mice. This study demonstrates that natural and existing antiviral immunity can be repurposed to fight tumors without the need for adjuvant, vaccination, or personalized identification of immunogenic tumor neoantigens. Citation Format: Pamela C. Rosato, Sathi Wijeyesinghe, J. Michael Stolley, Christine Nelson, Rachel L. Davis, Luke S. Manlove, Christopher A. Pennell, Bruce R. Blazar, Clark C. Chen, Melissa A. Geller, Vaiva Vezys, David Masopust. Repurposing antiviral T-cells to fight tumors [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 B182.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130745119","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}

{"title":"Abstract B156: Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma","authors":"A. Edwards, M. Skobe, Anita Rogic, M. Bosenberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B156","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B156","url":null,"abstract":"Melanoma cells disseminate through lymphatic vasculature into the regional lymph nodes early in disease progression. We found that a large subset of metastatic melanomas express chemokine receptor CCR8. Its principal ligand, CCL1, is constitutively expressed by lymphatic endothelial cells in the lymph node and is further upregulated by inflammation. The CCL1-CCR8 axis is an important checkpoint for melanoma lymph node metastasis, as an inhibition of CCR8 leads to arrest of melanoma cells in collecting lymphatic vessels and prevents lymph node metastasis. Among immune cells, CCR8 is predominantly expressed by regulatory T-cells (Treg) and by activated Th2 cells, and has been implicated mainly in allergic inflammation. Here we characterized CCR8+ immune cells and examined the role of CCR8 in mouse models of melanoma. Using inducible, genetically engineered (Tyr::CreER;BrafCAPtenloxPCtnnb1loxex3) and syngeneic mouse models of melanoma (B16F10) we characterized CCR8 expression on different immune cell subsets in primary tumors and in sentinel lymph nodes by flow cytometry. In primary tumors, CCR8 was exclusively expressed by CD4+ T-cells, with the highest percentage being FOXP3+CCR8+ Tregs. Increased numbers of CD4+FOXP3+CCR8+ Tregs were found in sentinel lymph nodes with metastases, compared to non-tumor-draining lymph nodes and lymph nodes from tumor-naive mice. This also corresponded with an increase in the total number of FOXP3+ T-regs in sentinel lymph nodes, compared to non-tumor draining lymph nodes. We then evaluated the role of CCR8 on B16F10 tumor growth. Tumor growth was significantly reduced in CCR8-/- mice compared to WT mice when anti-tumor immunity was stimulated with Poly(I:C). However, B16F10 tumor growth did not differ between untreated wild-type (WT) and CCR8 -/- mice. These results suggest that targeting CCR8+ Tregs may increase antitumor immune response. Further studies are required to determine the mechanism by which CCR8+ immune cells facilitate melanoma growth and to explore CCR8 as a therapeutic target in melanoma immunotherapy. Citation Format: Andrew K. Edwards, Mihaela Skobe, Anita Rogic, Marcus Bosenberg. Characterization and role of CCR8+ regulatory T-cells in mouse models of malignant melanoma [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 B156.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"99 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127026243","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}

{"title":"Abstract B159: Investigating the neuroimmune interaction between nociceptive neurons and dendritic cells","authors":"P. Hanč, Siyi Huang, U. V. Andrian","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B159","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B159","url":null,"abstract":"Nociceptive somatosensory neurons (nociceptors) have recently been established as controllers of immune responses in the context of infections, allergic airway inflammation, and imiquimod (IMQ)-induced psoriasiform skin inflammation. In most of these models, myeloid cells including dendritic cells (DCs) were shown to be a target of the actions of nociceptors. DCs form a bridge between the innate and adaptive immune system and it is mostly through their actions that the adaptive immune system gets activated. Notably, DCs were previously found to engage in a direct physical interaction with nociceptors as well as to be affected by soluble neuropeptides produced by the latter. Conflicting results have, however, been reported with regards to the function and the requirement of neuropeptides for the nociceptor:DC interaction under in vivo settings, suggesting a degree of context-dependency, while the requirement for physical interaction of the two cell types has not been tested. Inherently, in vivo approaches are not readily amenable for dissection of the molecular underpinnings of the interaction, and involvement of other, accessory cells can be difficult to exclude. Consequently, we have established an in-vitro nociceptor:DC co-culture system, which, compared to in vivo settings, allows us to dissect nociceptor:DC interactions in a less complex, reductionist setting.Using the in vitro co-culture setup, we show that dendritic cells and nociceptors engage in tight physical interactions, as well as that nociceptors produce chemo-attractant signals, which act directly on DCs. Further, we demonstrate that nociceptors enhance production of IL-6 and IL12-p40 cytokines by dendritic cells in response to IMQ, a TLR7 agonist. Strikingly, this effect was only apparent when DCs and nociceptors were allowed direct contact, suggesting a contact or proximity-based mechanism of interaction. In addition to IMQ, we identify other pathogen-associated molecular pattern (PAMP) molecules, which elicit a cytokine response that can be enhanced in the presence of nociceptors. Next, using live cell imaging, we showed that, as described previously, treatment of nociceptors with capsaicin, a TRPV-1 channel agonist, results in calcium flux and membrane depolarization of the neuronal cells. Strikingly, similar changes can be observed in DCs interacting with the neurons, while DCs alone do not exhibit any such behavior when treated with capsaicin. To further substantiate our findings, we utilized channelrhodopsin-expressing neurons, which can be activated by blue light without any other perturbations of the system. Importantly, light-induced activation of such neurons was sufficient to drive a calcium flux in the interacting DCs.Finally, to gain an unbiased view of the effects that nociceptors have on DCs, we performed RNA sequencing of DCs after co-culture. Strikingly, we observed profound changes in gene expression across DC subsets when DCs were cultured with neurons without an","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131021919","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}

{"title":"Abstract B176: Sequential immunotherapy and association with clinical outcomes in advanced-stage cancer patients","authors":"M. Bilen, D. Martini, Yuan Liu, C. Lewis, H. Collins, J. Shabto, M. Akce, H. Kissick, B. Carthon, W. Shaib, O. Alese, R. Pillai, C. Steuer, Christina Wu, D. Lawson, R. Kudchadkar, B. El-Rayes, V. Master, S. Ramalingam, T. Owonikoko, R. Harvey","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B176","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B176","url":null,"abstract":"Background: There are now six approved immune checkpoint inhibitors for several different malignancies including melanoma, head and neck cancer, lung cancer, and renal cell carcinoma. Given the increased number of available immunotherapeutic agents, more patients are presenting in clinic as candidates for sequential immunotherapy. However, the efficacy of sequential immunotherapy in a trial setting is unknown. We investigated the association between prior treatment with immune checkpoint inhibitors and clinical outcomes in patients treated with subsequent immunotherapy in a phase 1 clinical trial. Methods: We conducted a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute between 2009 and 2017. We included 49 patients with an immune checkpoint-indicated histology (melanoma, lung cancer, head and neck cancer, and bladder cancer). Patients were then analyzed based on whether they had received at least one immune checkpoint inhibitor prior to enrollment. Overall survival (OS) and progression-free survival (PFS) were calculated in months from immunotherapy initiation on trial to date of death and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard or logistic regression model. Covariates included age, presence of liver metastases, number of prior lines of systemic therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results: The median age was 67 years and most patients (78%) were men. The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). The majority (81%) of patients were RMH good risk. More than half of patients (n=27, 55%) had received at least one immune checkpoint inhibitor prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination therapy, and ten received multiple immune checkpoint inhibitors. In MVA, patients who had not received a prior immune checkpoint inhibitor had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p=0.010). These patients also trended towards longer PFS (HR: 0.86, CI: 0.39-1.87, p=0.699) and higher chance of CB (HR: 2.52, CI: 0.49-12.97, p=0.268). Immunotherapy-naive patients had substantially longer OS (24.3 vs 10.9 months) and PFS (5.1 vs. 2.8 months) than patients who had prior immunotherapy per Kaplan-Meier estimation. Conclusion: Optimal treatment options for oncology patients who progress on immune checkpoint inhibitors are lacking. In this study, patients who received at least one prior immune checkpoint inhibitor had worse clinical outcomes on immunotherapy-based phase 1 clinical trials than immune checkpoint-naive patients. This suggests that further development of immunotherapy combination the","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"88 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125515391","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}

{"title":"Abstract B161: Pseudoprogression of metastatic abdominal wall nodules in a patient with lung carcinoma treated with pembrolizumab","authors":"T. Hennedige, D. Tan, N. Iyer, Amit L. Jain","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B161","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B161","url":null,"abstract":"Pembrolizumab is a humanized IgG4 Kappa monoclonal programmed death receptor 1 directed antibody FDA approved for the first line treatment of metastatic non-small cell lung carcinoma (NSCLC) expressing >=50% PD-L1. Pseudoprogression in this context has rarely been reported. We encountered a patient within our community practice who received treatment with pembrolizumab and demonstrated radiologic features of pseudoprogression initially followed by clinical progression where upon histologic evaluation favored pseudoprogression over progression. The aims of this study are as follows: Firstly, to describe the clinico-pathologic-radiologic aspects of this patient’s treatment journey; secondly, to histologically characterize a lesion that was biopsied which showed clinical features of progression, but histologically, pseudoprogression; thirdly, to perform detailed flow cytometric analysis of lymphocytes obtained through the biopsy to characterize pseudoprogression. This is a single patient case study performed by reviewing clinical notes, radiology, and histology. Samples obtained on biopsy were further characterized by flow cytometry. A 72-year-old male patient with small volume metastatic squamous cell lung carcinoma with a tumor proportion score of 100% for PD-L1, was initially treated with radiation (20Gy) to palliate worsening dyspnea caused by airway obstruction. He had good local control with improvement in dyspnea and subsequently requested for observation only. Serial imaging revealed the development of an abdominal wall nodule. Before long, his metastatic disease became symptomatic and he was treated with first line pembrolizumab. Three weeks after his first dose, he presented with severe abdominal wall pain and a new palpable abdominal wall mass. Imaging performed confirmed the presence of a new abdominal wall mass in contrast to a reduction in size of his pulmonary lesions. This was thus assessed as pseudoprogression, and he was continued on treatment with radiologic response noted three weeks later in all lesions. He discontinued treatment due to cost at this point, and subsequently restarted treatment upon radiologic progression of disease. On restarting treatment, his abdominal wall nodule increased in size and ulcerated. True tumor progression was considered prompting biopsy of the abdominal wall nodule to enable stratification into clinical trials. However, histologic evaluation showed chronically inflamed granulation tissue with no microscopic evidence of malignancy suggesting pseudoprogression once again instead. The patient went on to receive radiotherapy to the abdominal wall nodule, and a serial scan demonstrated a reduction in size of the abdominal wall nodule and stable pulmonary disease. Flow cytometric analysis of biopsy tissue revealed predominantly CD45+ cells, 69.5% of which were CD3+. CD45+CD3+CD56- cells comprised CD4+ (27.9%), CD8+ (64.9%), CD4+PD1+ (46.7%), CD8+PD+ (37.7%). Further analysis by flow and mass cytometry i","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132758727","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}

{"title":"Abstract B175: Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model","authors":"Miika Martikainen, Di Yu, Mohanraj Ramachandran, G. Fotaki, M. Martikainen, A. Merits, M. Essand","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B175","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B175","url":null,"abstract":"Glioblastoma (GBM) is a devastating cancer of the central nervous system with no cure currently available. Oncolytic virotherapy with viruses that infect and destroy cancer cells provides a novel promising candidate therapy. We have previously shown that Semliki Forest virus (SFV) has therapeutic potency against orthotopic xenograft and syngeneic glioma models in mice. Here we show that SFV-infected cancer cells undergo immunogenic apoptosis, which triggers phagocytosis and maturation in co-cultured dendritic cells. SFV-killed GL261 mouse GBM cell lysate was also able to induce protective antitumor immune response in syngeneic mouse model, indicating that SFV oncolysis is immunogenic in vivo. By introducing mutations into the viral genome we have been able to produce a novel SFV clone which shows notably enhanced oncolytic potency in GL261 cells. As compared to the wild-type virus, the mutated SFV replicates faster and induces significantly stronger cytopathic effect. Robust viral replication and cytopathic effect were detected despite of activated type-I interferon signaling in the infected cells. This suggests that the enhanced SFV has increased resistance to antiviral response in mouse GBM cells. Viral proteins were detected by immunohistochemistry in orthotopic GL261 tumors after intratumoral injection of the mutated SFV virus. This provides evidence that the enhanced SFV is able to replicate in GL261 tumors in the face of antiviral in vivo microenvironment. Unwanted SFV replication in healthy brain cells can be inhibited by microRNA-mediated de-targeting. Taken together, the results indicate that oncolytic virotherapy with SFV can trigger antitumor immune responses, and support that SFV is a potent new candidate for oncolytic immunotherapy of GBM. These findings pave way for future clinical trials with oncolytic SFV. Citation Format: Miika Martikainen, Di Yu, Mohanraj Ramachandran, Grammatiki Fotaki, Minttu-Maria Martikainen, Andres Merits, Magnus Essand. Semliki Forest virus-mediated oncolytic immunotherapy in mouse GL261 glioblastoma model [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 B175.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"37 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133186590","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}

{"title":"Abstract B188: CMTM6, beyond a regulator of PD-L1 expression","authors":"Chong Sun, R. Mezzadra, R. Gomez-Eerland, I. Hofland, D. Peters, A. Broeks, H. Horlings, Wei Wu, A. Heck, T. Schumacher","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B188","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B188","url":null,"abstract":"Expression of PD-L1 by tumor cells and by infiltrating immune cells represents a critical feature of cancer immune evasion. In line with this, clinical targeting of the PD-1 – PD-L1 axis forms one of the most significant breakthroughs in cancer treatment of the past years. To study the mechanisms that regulate PD-L1 expression, we have previously performed a FACS-based genetic screen and identified CMTM6, a functionally-uncharacterized protein, as a novel regulator of PD-L1 protein levels. Furthermore, we observed that CMTM6 forms a molecular complex with PD-L1 and enhances the ability of PD-L1-expressing tumor cells to inhibit T-cells. However, apart from this important role for CMTM6 in PD-L1 regulation, our understanding of this protein remains highly limited. To further characterize CMTM6, we surveyed its expression in major tissues and organs in the human body. Analysis by IHC and flow cytometry shows thaT-cells in immune-privileged tissues and in primary and secondary lymphoid organs express CMTM6. In addition, we explored other biologic roles of CMTM6. We found CMTM6 positively regulates and co-immunoprecipitates with the co-stimulatory molecule CD58. Taken together, these findings indicate a broader role for CMTM6 in immune modulation. Citation Format: Chong Sun*, Riccardo Mezzadra*, Raquel Gomez-Eerland*, Ingrid Hofland, Dennis Peters, Annegien Broeks, Hugo M. Horlings, Wei Wu, Albert J. R. Heck, Ton N.M. Schumacher. CMTM6, beyond a regulator of PD-L1 expression [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 B188.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115845451","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}

{"title":"Abstract B154: Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses— Implications for the management of irAEs","authors":"M. Donia, T. H. Borch, H. D. Radic, C. Chamberlain, A. Gokuldass, I. Svane, A. Draghi","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B154","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B154","url":null,"abstract":"Background: Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of antitumor T-cells. Methods: The influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing capacity of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Results: Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively -46% and -62% in n=8) and tumor-killing ability (respectively -48% and -53% in n=6) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T-cell activation and tumor killing (respectively -20% in n=8 and -10% in n=6). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. Conclusions: Clinically relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology. Citation Format: Marco Donia, Troels H. Borch, Haja D. Radic, Christopher Chamberlain, Aishwarya Gokuldass, Inge Marie Stentoft Svane, Arianna Draghi. Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses— Implications for the management of irAEs [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 B154.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"129 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116033742","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}

{"title":"Abstract B151: Exploring the induction of immunogenic cell death (ICD) by high-intensity focused ultrasound (HIFU)","authors":"H. Dewitte, Y. Engelen, G. Lajoinie, L. C. Gomes‐da‐Silva, M. Versluis, S. Smedt, G. Kroemer, K. Breckpot, I. Lentacker","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B151","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B151","url":null,"abstract":"Immunogenic cell death (ICD) is an intriguing concept within cancer immunotherapy. Indeed, by inducing a specific means of cellular demise, a protective immune response can be triggered against the dying cells. As such, the dying cancer cells are—in a way—turned into a vaccine, attracting immune cells to the site of cell death, and activating them to trigger an anticancer immune response. Since the early discovery of ICD, more mechanistic insights into the hallmarks of ICD have been unraveled and several state-of-the-art cancer therapies have been identified as bona fide ICD inducers (1, 2).One of the cancer therapies which could be a potential candidate to induce ICD is high-intensity focused ultrasound (HIFU) (3). HIFU is currently used as a way of debulking solid tumors in a non-invasive, image-controlled and precise way without the use of ionizing radiation. Depending on the ultrasound parameters, tumor tissue can be ablated either in a mechanical (tissue disruption) or thermal way (heating and coagulative necrosis). Interestingly, there are some indications that HIFU may also affect the immune system: experiments in mice and man have shown attraction/activation of immune cells to/in the tumor site (4, 5). Of note: these immunostimulating effects were reported to be more prominent for mechanical HIFU than thermal HIFU. However, neither the mechanisms behind these observations, nor the possible link to the induction of ICD have been investigated. Therefore, the key aim of work is to investigate the potential of HIFU to induce ICD. Using a custom-designed HIFU set-up, we were able to—in a precise, automated and controlled way—expose B16F0 melanoma cells to HIFU in vitro. The HIFU-exposed tumor cells were subsequently evaluated for the occurrence of apoptosis and ICD hallmarks. More specifically, we evaluated the exposure of calreticulin (CRT) on the cell membrane and release of high mobility group box 1 (HMGB-1) and adenosine triphosphate (ATP). Our data show that application of mechanical HIFU protocols (using short, repeated ultrasound bursts) induce a significant fraction of apoptotic cells (as measured by a loss of mitochondrial membrane potential) within 4h after treatment. Importantly, already within the first hour after HIFU exposure, high levels of the ICD hallmark and Toll-like receptor 4 agonist HMGB-1 were found in the supernatant of the HIFU-treated cells, compared to untreated controls. To determine the effect of HIFU on ATP release, a quinacrine assay was performed to stain intracellular ATP-containing vesicles. Using flow cytometry, we observed that HIFU triggered exocytosis of these vesicles, with 2- to 3-fold reductions in quinacrine fluorescence at 4h and 24h after HIFU exposure, respectively. In addition, at 24h after HIFU exposure, >30% of the cells exposed CRT on the outer leaflet of the cell membrane, which was a drastic increase compared to blanks ( Citation Format: Heleen Dewitte, Yanou Engelen, Guillaume Lajoinie, Ligia","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"11 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115481227","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}