bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B174: Co-expression of stimulators and inhibitors of T-cell activation in melanoma
Authors: Maniyar Rachana , Freund Robert , Malhotra Aryan , Chakraborty Sanjukta , Geliebter Jan , Wallack Marc , Tiwari Raj K. 
Published: February 2019

Abstract
Melanoma, one of the most aggressive skin cancers, has steadily been on the rise over the last three decades. With limited treatment options, the recent impetus in immuno-oncology drugs, especially checkpoint inhibitors, has changed the treatment landscape. While anti-CTLA4 and anti-PD1 demonstrated success in clinic, the search for additional targets is needed to enable potent comprehensive curative combination therapies. Our laboratory has characterized and screened five primary patient-derived melanoma cell lines, MEL-2, MEL-V, 3MM, KFM, and GLM-2. While immunomodulatory molecules are canonically present on antigen presenting cells and T-cells, increasing evidence suggests that they are not expressed in isolation. In an effort to identify immunomodulatory molecules expressed on our primary melanoma cells, a comprehensive RT-PCR screen of 29 co-inhibitory and co-stimulatory molecules was carried out. Several molecules including CD160, CD226, TIM1, HVEM, and BTLA were seen to be differentially expressed in melanoma cells compared to normal melanocytes at the mRNA level. Western blots and immunocytochemistry validated the differential expression of these molecules at the protein level. 50-80% of melanoma cases are positive for the BRAFV600E mutation, and are treated with a small molecule inhibitor of the mutated BRAF, vemurafenib (PLX4032). Treatment of these cells with PLX4032 led to an upregulation of transcription factors MITF and AP-1, as well as immunomodulatory molecules, CD160, CD226, TIM1, HVEM, and BTLA, a phenomenon seen only in cells positive for the BRAFV600E lesion. MITF and AP-1, owing to the binding sites present in the promoter regions of these molecules, can drive their expression upon treatment with PLX4032. These additional immune-regulatory molecules of T-cell activation and/or immune tolerance mechanisms are potential targets for a combination therapy with PLX4032 in melanoma patients positive for the BRAFV600E genetic lesion. Our future directions aim to elucidate the role of these molecules on the tumor cells and devise an effective combination with small-molecule inhibitors and immunotherapies.
Citation Format: Rachana Maniyar, Robert Freund, Aryan Malhotra, Sanjukta Chakraborty, Jan Geliebter, Marc Wallack, Raj K. Tiwari. Co-expression of stimulators and inhibitors of T-cell activation in 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 B174.
Abstract B177: Analysis of immunogenic cell death (ICD) induced in multiple myeloma cells
Authors: Matsushita Maiko , Kashiwazaki Sho , Kamiko Satoshi , Uozaki Ryo , Ichikawa Daiju , Hattori Yutaka 
Published: February 2019

Abstract
Background: Development of novel drugs, such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), or monoclonal antibodies, has prolonged survival of multiple myeloma (MM) patients. However, high-risk patients harboring del 17, t(14;17), or t(11;14) still have poor prognosis. Therefore, clarification of the drugs that could potentiate the effect of these treatments is necessary. Several drugs have been reported to cause cell surface expression of calreticulin (CRT), release of high mobility group box 1 (HMGB 1) and ATP, activating an immune response, which is called immunogenic cell death (ICD). However, there is almost no information on ICD in MM. The purpose of this study is to investigate whether anti-MM drugs can induce not only direct cell-killing effect but also immunomodulatory effects in high-risk MM cells. Methods: High-risk myeloma cell line, MUM24 was treated with dexamethasone, melphalan, lenalidomide, bortezomib, carfilzomib, and panobinostat. Expression of cell surface CRT and HMGB1 release were detected using flow cytometry and Western blotting, respectively. We then co-cultured DiD-labeled monocyte-derived dendritic cells with GFP-induced MUM24 treated with each drug and evaluated phagocytosis of DCs using fluorescence microscope. Results: After treatment with drugs, bortezomib and carfilzomib induced higher expression of CRT and release of HMGB1 in MUM24 compared with other drugs. We also observed that DCs could engulf MUM24 cells treated with carfilzomib. Conclusion: Our results suggest that PIs, such as bortezomib or carfilzomib, could not only kill MM cells but also induce ICD. These effects are expected to improve the prognosis of MM patients by evoking strong immune response against MM cells.
Citation Format: Maiko Matsushita, Sho Kashiwazaki, Satoshi Kamiko, Ryo Uozaki, Daiju Ichikawa, Yutaka Hattori. Analysis of immunogenic cell death (ICD) induced in multiple myeloma 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 B177.
Abstract B188: CMTM6, beyond a regulator of PD-L1 expression
Authors: Sun Chong , Mezzadra Riccardo , Gomez-Eerland Raquel , Hofland Ingrid , Peters Dennis , Broeks Annegien , Horlings Hugo M. , Wu Wei , Heck Albert J. R. , Schumacher Ton N.M. 
Published: February 2019

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.
Abstract B196: Examining proteasome sensitivity of lymphoid malignancy: Ubiquilin 1 (Ubqln1) is required for BCR-induced proliferation of B cells
Authors: Whiteley Alexandra M. , Brown Eric , Finley Daniel 
Published: February 2019

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.
Abstract B201: Exploration and exploitation of macrophage death pathways: Infection by Mycobacterium tuberculosis as a model
Authors: Zander Ryan , Schauder David , Xin Gang , Nguyen Christine , Wu Xiaopeng , Cui Weiguo 
Published: February 2019

Abstract
Macrophages can impact the development of tumors and their responses to therapy. However, we lack a full understanding of how macrophage activation and survival are regulated and might be therapeutically modulated. To address these questions, we turned to a host-pathogen interaction that is likely to have impacted the evolution of these processes: infection by Mycobacterium tuberculosis (Mtb), the leading cause of death from infection. Once internalized by macrophages, Mtb resists killing by macrophages and replicates within them. Ultimately, Mtb infection results in death of macrophages, allowing dissemination of the pathogen to other cells. To explore how Mtb induces macrophage cell death and how macrophage cell death might impact host defense against Mtb, we performed a genome-wide CRISPR-Cas9 recessive genetic screen in RAW264.7 macrophages. We discovered that the absence of components of the type I interferon signaling pathway, including the IFN-α/β receptor (IFNAR), delays Mtb-induced cell death. It is known that Mtb infection induces macrophages to produce type I interferon. Our finding directly links type I interferon signaling pathway and Mtb-induced macrophage death. We are currently working on the mechanism of the type I IFN-induced death of bacterially-stimulated macrophages. Meanwhile, we are testing blockers of this pathway as host-directed therapy against TB and have seen striking protective effects of anti-IFNAR1 mAb in Mtb-infected mice, whether the mAb is administered before or after infection. Further exploration of the protective effect of anti-IFNAR mAb could point to an antibody-based, host-directed therapy. Acknowledgment: We thank Prof. R. Schreiber, Washington University, for facilitating access to anti-IFNAR mAb.
Citation Format: Ryan Zander, David Schauder, Gang Xin, Christine Nguyen, Xiaopeng Wu, Weiguo Cui. Exploration and exploitation of macrophage death pathways: Infection by Mycobacterium tuberculosis as a 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 B201.
Abstract B202: Defining the role of IL-27 signaling on responses to metastatic melanoma
Authors: Phan Anthony T. , Hunter Christopher A. 
Published: February 2019

Abstract
Checkpoint blockade and cellular therapies for cancer treatment have yielded impressive clinical results. These approaches harness the ability of T-cells, critical mediators of the body’s immune response to infection, to eliminate tumors. Entry of T-cells into the tumor microenvironment exposes them to an array of regulatory signals that impact T-cell differentiation and function. The immunomodulatory cytokine, interleukin 27 (IL-27), produced by tumor cells and immune cells, is a critical regulator of the immune system. A complex literature exists regarding the role of IL-27 in tumor responses and the conflicting conclusions from these studies can be attributed to differences in tumor models and a lack of lineage-specific genetic tools to dissect the impact of IL-27 signaling on particular cell types. We find that IL-27 receptor alpha (WSX1)-deficient mice exhibit reduced tumor burdens following intravenous administration of B16 melanoma in comparison to wildtype mice. Further, the reduced number of macroscopic nodules corresponds with reduced tumor area within the lungs. Analysis of IL-27 reporter mice reveals a population of nonalveolar macrophage/monocytes to be the primary source of IL-27 in the lung as early as day 10 following B16 melanoma challenge. The production of IL-27 in the lung following tumor challenge and the improved resistance to intravenous dissemination of B16 melanoma by WSX1-deficient mice suggests production of IL-27 suppresses immune responses to melanoma within the lung. In line with these data, we find that tumor nodules in the lungs of WSX1-deficient mice have increased infiltration of CD3+ cells observed by histologic analysis in comparison to tumor nodules in wild-type mice. These data support a model where IL-27 suppresses the infiltration or activity of T-cells responding to metastatic melanoma and suggest that novel strategies targeting IL-27 signaling in the tumor microenvironment may synergize with current immunotherapy approaches to improve T-cell responses to tumors.
Citation Format: Anthony T. Phan, Christopher A. Hunter. Defining the role of IL-27 signaling on responses to metastatic 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 B202.
Abstract IA12: CAR T-cell therapy for lymphoma and multiple myeloma
Authors: Kochenderfer James N. 
Published: February 2019

Abstract
Chimeric antigen receptors (CARs) are fusion proteins that incorporate antigen-binding domains and T-cell signaling domains. The first CAR T cells to be shown to be clinically effective targeted the B-cell antigen CD19. Anti-CD19 CAR T cells have been effective against all major types of B-cell lymphomas, and anti-CD19 CAR T cells have now obtained Food and Drug Administration (FDA) approval for treatment of the most common type of lymphoma, diffuse large B-cell lymphoma. This approval was based on clinical results that showed an approximately 50% complete remission rate of anti-CD19 CAR T-cell therapy for diffuse large B-cell lymphoma. These responses have been durable. Eleven of twelve patients who obtained complete remissions on a phase 1 trial of anti-CD19 CAR T cells are still progression-free 13 to 36 months after treatment (Kochenderfer et al. Journal of Clinical Oncology, 2017). Even more durable remissions have occurred in a small number of patients in an early cohort of anti-CD19 CAR therapy. Four patients with remissions of 38 to 56 months will be presented. These patients are particularly interesting because 3 of the 4 patients with long remissions have had recovery of normal B cells while the complete remissions have continued. This result shows that remissions of diffuse large B-cell lymphoma can continue after disappearance of a functional anti-CD19 CAR T-cell response. Beyond CD19, active CAR T-cell therapy for multiple myeloma has been developed by targeting B-cell maturation antigen (BCMA). Anti-BCMA CAR T cells have undergone rapid clinical development since first being reported in 2013 (Carpenter et al. Clinical Cancer Research, 2013). Clinical results of the first-in-humans clinical trial of anti-BCMA CARs (Brudno et al. Journal of Clinical Oncology, 2018) will be presented, and future plans for multiple myeloma CAR T-cell therapies will be discussed.
Citation Format: James N. Kochenderfer. CAR T-cell therapy for lymphoma and multiple myeloma [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 IA12.
Abstract IA18: Inactivation of DNA repair to improve immune surveillance
Authors: Bardelli Alberto 
Published: February 2019

Abstract
When metastatic cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? Addressing this question means considering as a target not “only” individual oncogenes but also the evolving nature of human tumors. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor’s evolution, the emergence of drug resistance can be controlled. We find that to have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. Another approach is to unleash the ability of the immune system to recognize drug resistant cells. We tested this possibility in syngeneic mouse models of CRC sensitive to targeted therapies. Our findings indicate that inactivation of DNA repair mechanisms and manipulation of mutational loads can trigger immune surveillance and prolonged therapeutic responses. We postulate that rationally combined targeted and immuno-therapies can restrain tumor evolution, and can limit the emergence of drug resistance thus leading to long-term responses.
Citation Format: Alberto Bardelli. Inactivation of DNA repair to improve immune surveillance [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 IA18.
Abstract IA20: Targeting the immune microenvironment in breast cancer
Authors: Loi Sherene , Savas Peter 
Published: February 2019

Abstract
Immunotherapy has revolutionized cancer treatment, but the benefits are not ubiquitous or absolute. In breast cancer, higher levels of lymphocytic infiltrate confer significant prognostic advantage, predict response to chemotherapy in early stage disease and are associated with benefit from PD-1 inhibition. To enhance the modest benefits of immunotherapy seen in breast cancer thus far, it is expected that a greater understanding of the immune subpopulations in the tumor microenvironment will be necessary, emphasizing that the quality and quantity of tumor infiltrating lymphocytes are important. We have profiled the T cell infiltrate in primary and metastatic breast cancers, using flow cytometry, single cell mRNASeq, multiplex immunohistochemistry and bulk RNASeq on flow sorted CD8 populations. In this work, we found that CD8 T cells display tissue resident specialization. In particular, we confirmed the presence of a CD8 T cell population with tissue resident memory features. This population was notable for high expression of T cell checkpoint receptors and cytotoxic markers, active proliferation, and a distinct T cell receptor repertoire in contrast to CD8 effector memory T cells. A gene signature derived from this population was found to be prognostic in early stage breast cancer and associated with benefit from PD-1 checkpoint inhibition in melanoma. We find that single cell profiling in human samples is a powerful technique which unveils tissue resident aspects of the anti-cancer immune response. This approach may lead to better immunotherapy biomarkers and optimization of immunotherapeutic strategies.
Citation Format: Sherene Loi, Peter Savas. Targeting the immune microenvironment in breast 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 IA20.
Abstract IA26: Combination immunotherapy of cancer caused by human papilloma virus
Authors: Melief Cornelis J.M. 
Published: February 2019

Abstract
We have completed a chemo-immunotherapy study in 70 patients with late stage HPV16+ cervical cancer. Three HPV16-SLP vaccine doses, consisting of 13 overlapping peptides covering the amino acid sequence of the oncogenic proteins E6 and E7 of HPV16, were given 2 weeks after the second, third and fourth cycle of standard chemotherapy (carboplatin, AUC 6; paclitaxel 175 mg/ m2). The vaccine was administered subcutaneously as an emulsion in adjuvant Montanide ISA-51. Cohorts of 12 patients were vaccinated with each of 4 dose levels (20, 40, 100 and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the E6 and E7 protein sequence. Two additional cohorts of 6 patients each were vaccinated with the most promising doses of 40 and 100 µg/ peptide. A marked and significant positive correlation was observed between the strength of the vaccine-induced T cell immune response and overall survival. No such correlation was observed between the strength of the T cell response against common recall antigens and survival. In addition a remarkably high proportion of patients survived beyond 2 years after the start of therapy. We also completed a combination study of this vaccine with checkpoint blocker nivolumab (anti-PD-1) in patients with incurable HPV16+ oropharyngeal cancer. Of 22 treated patients, 2 achieved a durable complete clinical response (CR) by resist criteria and 6 a partial response (PR). The overall response rate was 36%, approximately twice that reported for nivolumab as monotherapy in a similar category of patients with oropharyngeal cancer. This combination treatment was associated with robust HPV16 E6/E7-specific T cell responses.
Citation Format: Cornelis J.M. Melief. Combination immunotherapy of cancer caused by human papilloma virus [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 IA26.