bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B16: Identification of tumor-specific antigens shared by induced pluripotent stem cells
Authors: Apavaloaei Anca , Hardy Marie-Pierre , Larouche Jean-David , Zhao Qingchuan , Vincent Krystel , Laverdure Jean-Philippe , Durette Chantal , Lanoix Joel , Thibault Pierre , Perreault Claude 
Published: March 2020

Abstract
The development of cancer immunotherapeutics is limited by the tumor-specific antigen (TSA) discovery. Cancer cells and pluripotent stem cells, i.e., embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), show a significant transcriptomic overlap. Indeed, when used as prophylactic vaccines in another study, iPSCs prevented tumor growth in mouse models of lung, breast, and skin cancer, suggesting that we could mine iPSCs for the discovery of TSAs. We use a recently developed proteogenomic approach combining RNA-sequencing and mass spectrometry to characterize the immunopeptidome (MHC class I-associated peptides) of iPSCs. Analyses of hitherto one human iPS cell line allowed us to identify 9 MHC class I-associated antigens that were not expressed by normal somatic tissues and thus are likely immunogenic. 50% of these antigens were highly expressed in different cancer types from The Cancer Genome Atlas, highlighting their potential for cancer immunotherapy. Expression of these TSAs resulted from aberrant expression of noncoding genomic regions and not from mutations, making them ideal candidates for antigen-based cancer vaccines. Our study indicates which stem cell features present in cancer cells might be harnessed for cancer immunotherapy. Moreover, we show for the first time that the immunopeptidome of iPSCs reflects the state of pluripotency. Cancer stem cells are known to drive disease relapse after treatment, while cancer circulating cells possessing pluripotent stem cell features are more efficient at producing metastases. These factors indicate that treatments targeted at stemness could improve clinical outcome, and that iPSC-informed TSAs hold promise for prophylactic and therapeutic cancer vaccines.
Citation Format: Anca Apavaloaei, Marie-Pierre Hardy, Jean-David Larouche, Qingchuan Zhao, Krystel Vincent, Jean-Philippe Laverdure, Chantal Durette, Joel Lanoix, Pierre Thibault, Claude Perreault. Identification of tumor-specific antigens shared by induced pluripotent stem cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B16.
Abstract B17: Identification of drugs that synergize with immunotherapies
Authors: Sahu Avinash D. , Wang Xiaoman , Flaherty Keith , Klomp Jan , Oubrie Arthur , Liu Shirley 
Published: March 2020

Abstract
Introduction: Immune checkpoint blockers (ICB) revitalize the immune system against cancer cells and have led to breakthroughs in cancer treatment and unprecedented survival benefits. However, they are ineffective in the majority of advanced cancer patients. For designing new treatments combining ICB with cancer drugs for treating late-stage cancer patients, there is an unmet need for a systematic approach to identify immunomodulatory drugs. Addressing this, we developed DeepImmune, the first in silico predictor of immunomodulatory drugs.
Methods: DeepImmune engages artificial intelligence (AI) to build a novel ICB response predictor and employs drug-induced transcriptomic changes to identify drugs that synergize with ICB and prioritize them for clinical trials. The parameters of the predictor are trained on 32,000 non-ICB patients’ data and transferred to ICB setting, where the parameters are fine-tuned on data from 1,000 ICB patients.
Results: We applied DeepImmune to 1,600 investigational drugs that explicated oxidative phosphorylation (Oxphos) inhibition as immunomodulatory. DeepImmune predicted inhibition of Oxphos in tumors would enhance antigen presentation, infiltration of CD8-T and proinflammatory macrophage, and will decrease T-regs and MDSC in tumor microenvironment. We validated these predictions in patient tumor data. Furthermore, the analysis of single-cell RNA-seq revealed that a decrease in Oxphos was associated with polarization toward proinflammatory (M1) macrophage. Drug inhibition of Oxphos in immune cold murine models (4T1 and B16F10) enhanced T-cell infiltration, decreased T-regs, and MDSC in tumors. The Oxphos inhibition-induced immune response in mouse models was accompanied by tumor regression, validating DeepImmune’s predictions.
Conclusion: Our analysis suggests that Oxphos inhibition can turn immune-cold tumor hot. Importantly, AI could be engaged to identify new immunomodulatory small molecules, which will help to rationalize immuno-oncology clinical trials and accelerate therapy optimization.
Citation Format: Avinash D. Sahu, Xiaoman Wang, Keith Flaherty, Jan Klomp, Arthur Oubrie, Shirley Liu. Identification of drugs that synergize with immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B17.
Abstract B29: The importance of epitope spreading in the generation of effective antitumor immunity in mice treated with combination immunotherapy
Authors: Lee Karin L. , Palena Claudia , Schlom Jeffrey , Hamilton Duane H. 
Published: March 2020

Abstract
Recent clinical successes of PD-1/L1 and CTLA-4 blockade have demonstrated the potential of immunotherapies for the treatment of cancer. Research suggests the clinical efficacy of these checkpoint blockade therapies requires the presence of tumor-reactive T cells prior to therapy. It is thought that these tumor-reactive T cells primarily recognize nonsynonymous mutations (neoepitopes) uniquely expressed by a patient’s tumor. Unfortunately, at present the majority of patients fail to respond to checkpoint blockade, and it is hypothesized that one can improve their efficacy by combining them with vaccines targeting neoepitopes. Using the MC38 murine colon cancer model, we previously showed that an effective antitumor immunity could be generated when combining either a peptide or recombinant adenoviral-based vaccine targeting neoepitopes with three rationally selected immune-oncology agents. We utilized an IL-15 superagonist (N-803) to promote the generation and expansion of T cells and a tumor-targeted IL12 (NHS-IL12) and PD-L1 blockade to facilitate T-cell expansion and function within the tumor microenvironment. This multifaceted treatment regimen was effective at inducing tumor clearance in the majority of animals treated. In the present study, we examine the immune response in animals that fail to respond to our treatment regimen. By analyzing the spread of immunity to neoepitopes expressed by the MC38 tumor, but not contained within the vaccine, we were able to correlate treatment failures to less diversity in the antitumor immune response. To examine this observation more closely, tumor-bearing mice were treated with different combinations of neoepitope vaccine, N-803, PD-L1 blockade, and NHS-IL12, to ascertain which components of the combination therapy facilitated epitope spreading. We also examined which cell populations were able to cooperate with tumor-reactive CD8+ T cells to promote and/or inhibit epitope spread. Our observations demonstrate the importance of a diverse antitumor immune response and offers insights on how one might increase the diversity of the antitumor immune response following treatment with immune-oncology agents. These studies were performed in collaboration with NantOmics, NantBio and ImmunityBio, and EMD Serono as a part of Collaborative Research and Development Agreements (CRADA) with the NCI.
Citation Format: Karin L. Lee, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. The importance of epitope spreading in the generation of effective antitumor immunity in mice treated with combination immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B29.
Abstract B42: Human CD141+ dendritic cells (cDC1) are impaired in advanced melanoma patients but can be targeted to increase efficacy of anti-PD-1 checkpoint inhibitor therapy
Authors: O’Brien Liam , Lee Yoke Seng , Walpole Carina , Rojas Ingrid Leal , Masterman Kelly-Anne , Atkinson Victoria , Barbour Andrew , Radford Kristen 
Published: March 2020

Abstract
Dendritic cells (DCs) as professional antigen-presenting cells with unique T-cell stimulatory capacity represent a potential means by which to improve response rates towards immune checkpoint inhibitor antibodies (ICIs) such as anti-PD-1 (pembrolizumab) in melanoma. The conventional type 1 DC subset (cDC1) is indispensable for the efficacy of ICIs in animal models; however, very little is known about the role of cDC1 in human cancer patients. To address this, we developed a whole-blood assay for quantifying and characterizing human DC subsets (cDC1, cDC2 and plasmacytoid DCs [pDCs]) by flow cytometry and compared these in healthy donors and stage III and IV metastatic melanoma patients. cDC1 and pDC numbers were significantly reduced in stage IV melanoma patients compared to healthy controls. Moreover, cDC1s in melanoma patients were selectively impaired in their ability to upregulate CD83 expression after stimulation with TLR3 and TLR7/8 agonists ex vivo. Although DC numbers did not correlate with responses to anti-PD-1 and/or anti-CTLA-4 ICIs, their numbers and capacity to upregulate CD83 declined further during treatment in nonresponding patients. To examine whether harnessing cDC1 could improve responses to ICIs in human melanoma, we developed a humanized mouse model by engrafting immunodeficient NSG-SGM3 mice with CD34+ hematopoietic stem cells from umbilical cord blood followed by transplantation of a human melanoma cell line. Treatment with anti-PD-1 in this model was ineffective at controlling tumor growth, but efficacy was enhanced by indirectly expanding and activating DCs in vivo with Flt-3 ligand (Flt3L) and TLR3 agonist polyI:C. Moreover, intratumoral injection of cDC1s, but not cDC2s, resulted in reduced tumor growth when combined with anti-PD-1 treatment. Together, these data illustrate impairments in cDC1 in advanced melanoma patients and provide rationale for harnessing them to increase immunogenicity and response rates to ICIs.
Citation Format: Liam O’Brien, Yoke Seng Lee, Carina Walpole, Ingrid Leal Rojas, Kelly-Anne Masterman, Victoria Atkinson, Andrew Barbour, Kristen Radford. Human CD141+ dendritic cells (cDC1) are impaired in advanced melanoma patients but can be targeted to increase efficacy of anti-PD-1 checkpoint inhibitor therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B42.
Abstract B47: CHIME screening identifies PTPN2 as a novel regulator of antitumor immunity
Authors: LaFleur Martin , Nguyen Thao , Coxe Matthew , Miller Brian , Yates Kathleen , Gillis Jacob , Sen Debattama , Doench John , Haining Nicholas , Sharpe Arlene 
Published: March 2020

Abstract
Despite the significant clinical responses observed with checkpoint blockade, there is an urgent need to identify new therapeutic targets in immune cells for combination therapies. However, the use of functional genomic approaches in immune cells to discover immunotherapy targets is limited by inefficient vector delivery or perturbation of cell states. To circumvent these limitations, we developed CHIME: CHimeric IMmune Editing, a bone marrow chimeric CRISPR-Cas9 delivery system, to rapidly evaluate gene function in innate and adaptive immune cells in vivo without prior ex vivo manipulation. This approach enables efficient deletion of genes of interest in major immune lineages without altering immune development or function. To discover novel immunotherapy targets we performed an in vivo pooled genetic screen for negative regulators of CD8+ T-cell responses to LCMV Clone 13 viral infection. We found that deletion of the phosphatase Ptpn2 enhances CD8+ T-cell responses to chronic pathogens and cancer. In models of both chronic viral infection and transplantable tumors, Ptpn2 null CD8+ T cells expand more and show increased expression of effector genes compared to wild-type cells. Consistent with this, in the LCMV Clone 13 model, Ptpn2 deletion in CD8+ T cells affects the differentiation and expansion of exhausted subpopulations by increasing IFN-I signaling. Furthermore, deletion of Ptpn2 in the immune system induces a CD8+ T cell-dependent clearance of tumors and synergizes with PD-1 immune checkpoint blockade. Our results suggest that therapeutic inhibition of Ptpn2 in immune cells may enhance CD8+ T-cell effector function and mediate antitumor immunity to improve tumor control. More generally, these findings suggest that this genetic platform can enable rapid target discovery through pooled loss-of-function screening in immune cell lineages in vivo and presents a novel target for potential immune based therapies.
Citation Format: Martin LaFleur, Thao Nguyen, Matthew Coxe, Brian Miller, Kathleen Yates, Jacob Gillis, Debattama Sen, John Doench, Nicholas Haining, Arlene Sharpe. CHIME screening identifies PTPN2 as a novel regulator of antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B47.
Abstract B48: PI3Kδ-specific inhibitors may act as adjuvants in the immunotherapy of glioblastoma
Authors: Azam Zulfikar , Wei Shao , To Tony 
Published: March 2020

Abstract
Glioblastoma is the most devastating form of primary brain tumor. Despite surgery, radiotherapy, and concomitant temozolomide chemotherapy, the survival rate remains disappointing. Multiple factors including a diverse array of signaling pathways play significant roles in glioblastoma pathogenesis. Of note, the phosphoinositide 3-kinase (PI3K) signaling pathway is often aberrant in glioblastoma, leading to uncontrolled cell proliferation, migration, and invasion into nearby normal brain tissues. The PI3Kδ isoform, predominantly found in leukocytes, is expressed in a number of tumors including glioblastoma. We had previously shown that PI3Kδ is also expressed in glioma cells such as the U87-MG cell line. Using siRNA knockdown technique, we demonstrated that it is important in glioma cell migration and invasion. Interestingly, its expression has been reported to associate with glioma cell resistance to erlotinib. To further study the mechanistic role of PI3Kδ in glioma pathogenesis, we created two knockout cell strains of U87-MG by CRISPR-Cas9 technology. We performed global transcriptome and pathway analysis comparing the parent cell line U87-MG with these knockout cell strains. Our results showed that the mRNA expression of Pleckstrin 2 (PLEK2) is dramatically reduced in PI3Kδ knockout cells. This is confirmed by quantitative RT-PCR. Western blot analysis showed that PLEK2 protein level is reduced by more than 90% and the phosphorylation of Akt at 308, but not 473, is also reduced. PLEK2 contributes to lamellipodia formation and cell spreading via actin cytoskeleton rearrangement, ultimately affecting cell migration and invasion. Our recent findings further strengthen the important role of PI3Kδ in glioma cell motility. It has been shown recently that inhibition of PI3Kα/δ directly enhances effector CD8+ T-cell activity. Thus, use of PI3Kδ-specific inhibitors may reduce expression of PLEK2 thereby reduces glioma cell migration and at the same time promotes antitumor immunity. PI3Kδ inhibitors may also be used as adjuvants together with immune checkpoint inhibitors such as pembrolizumab to prolong the survival of glioblastoma patients.
Citation Format: Zulfikar Azam, Shao Wei, Tony To. PI3Kδ-specific inhibitors may act as adjuvants in the immunotherapy of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B48.
Abstract B5: Reversing epigenetic gene silencing to overcome immune evasion in CNS malignancies
Authors: Ratnam Nivedita M. , Sonnemann Heather M. , Gilbert Mark R. , Giles Amber J. 
Published: March 2020

Abstract
Glioblastoma (GBM) is a lethal brain malignancy, and standard of care only offers a modest survival benefit. Emerging evidence of immune surveillance in the brain has prompted investigation of immunotherapy as a potential treatment strategy. However, preliminary studies have demonstrated impaired immune cell trafficking to the tumor, making GBMs immunologically “cold.” One mechanism of immune evasion by the tumor is to epigenetically silence the expression of chemoattractant cytokines. Previous studies in ovarian and prostate cancer have successfully established the ability of GSK126, a small-molecule inhibitor of histone methyl transferase EZH2, to promote tumor T-cell infiltration and subsequent antitumor response. Mechanistically, GSK126 was shown to promote expression of interferon gamma (IFN gamma)-induced chemokines CXCL9 and CXCL10. In the present study we evaluated the therapeutic efficacy of GSK126 in preclinical models of GBM. Our studies determined that treatment of murine and human glioblastoma cell lines with GSK126 increased IFN gamma-mediated gene expression of CXCL9 and CXCL10. Transwell migration assays performed using human T cells demonstrated increased T-cell migration when exposed to conditioned medium from tumor cells treated with GSK126 and IFN gamma. In vivo, efficacy of GSK126 was tested in combination with anti-PD-1 antibody in C57Bl/6 immunocompetent mice subcutaneously implanted with the syngeneic glioma cell line CT2A. Mice treated with the combination of GSK126 and anti-PD-1 antibody showed a significant decrease in tumor volume and improved overall survival. Tumors treated with combination therapy showed increased infiltration of CD8+ IFN gamma expressing T cells and increased CXCR3+ migratory T cells in the tumor-draining lymph node. Interestingly, treatment of mice with intracranial CT2A tumors with GSK126 alone resulted in small tumors with better prognosis. Treatment-related survival benefit was lost in immune-compromised mice, suggesting that efficacy depended upon drug-related increased lymphocyte trafficking and subsequent T cell-mediated antitumor response. Analysis of post-treatment tumor by LC-MS confirmed that GSK126 crosses the blood-brain barrier. Taken together, our data suggest a potential synergistic therapeutic role for GSK126 in glioblastoma by enhancing current immunotherapy regimens with reversing the epigenetic changes that enable immune cell evasion with resultant increases in immune cell trafficking to the tumor.
Citation Format: Nivedita M. Ratnam, Heather M. Sonnemann, Mark R. Gilbert, Amber J. Giles. Reversing epigenetic gene silencing to overcome immune evasion in CNS malignancies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B5.
Abstract B51: Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4
Authors: Wang Zhiyong , Wu Victoria H. , Allevato Michael M. , Gilardi Mara , Saddawi-Konefka Robert , He Yudou , Callejas-Valera Juan Luis , Vitale-Cross Lynn , Martin Daniel , Amornphimoltham Panomwat , Mcdermott James , Goto Yusuke , Molinolo Alfredo A. , Sharabi Andrew B. , Cohen Ezra E.W. , Chen Qianming , Lyons Guy , Alexandrov Ludmil B. , Gutkind J. Silvio 
Published: March 2020

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that &gt;70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.
Note:This abstract was not presented at the conference.
Citation Format: Zhiyong Wang, Victoria H. Wu, Michael M. Allevato, Mara Gilardi, Robert Saddawi-Konefka, Yudou He, Juan Luis Callejas-Valera, Lynn Vitale-Cross, Daniel Martin, Panomwat Amornphimoltham, James Mcdermott, Yusuke Goto, Alfredo A. Molinolo, Andrew B. Sharabi, Ezra E.W. Cohen, Qianming Chen, Guy Lyons, Ludmil B. Alexandrov, J. Silvio Gutkind. Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B51.