bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B81: Efficacy of nivolumab, pembrolizumab, and atezolizumab against MC38 colon cancer expressing human PD-1 in transgenic C57BL/6 mice expressing human PD-1 and PD-L1 checkpoint genes
Authors: Stackhouse Murray , Green Ted , Liu Jay , Hammond Charlotte , Durbin LaJuana , Chen Anna , Koratich Mike 
Published: June 2021

Abstract
The human checkpoint genes PD-1 and PD-L1 have been the target of extensive research for the treatment of human malignancies. Checkpoint inhibitor therapy has shown great promise in the clinic. Animal models that can use the human clinical antibodies will be beneficial for evaluating new therapies. A novel transgenic mouse model was developed that expresses the human PD-1 and PD-L1 in place of the murine genes. Additionally, a murine MC38 colon tumor cell line was modified to express human PD-L1. We evaluated the efficacy of human check point antibodies nivolumab, pembrolizumab, and atezolizumab in the transgenic animal model with modified MC38 colon cancer cells. Five hundred thousand transgenic MC38 cells were implanted in the C57BL/6 PD-1/PD-L1 knock in mice and allowed to grow for three days. The tumor-implanted mice were treated with nivolumab and pembrolizumab at 100 μg per animal and atezolizumab at 1 mg per animal on Days 3, 7, 10, and 14. Treatment with nivolumab and pembrolizumab caused tumor regression by Day 17. Growth inhibition was 84%, 58%, and 94% on Day 17 for nivolumab, atezolizumab, and pembrolizumab, respectively, compared to the control animals. There was no significant body weight loss and no signs of toxicity in any of the treated animals. We have shown that both PD-1 and PD-L1 inhibitors are effective in treating genetically modified MC38 colon tumors in transgenic mice. Further research will involve combining each of the checkpoint antibodies with various chemotherapeutic agents.
Citation Format: Murray Stackhouse, Ted Green, Jay Liu, Charlotte Hammond, LaJuana Durbin, Anna Chen, Mike Koratich. Efficacy of nivolumab, pembrolizumab, and atezolizumab against MC38 colon cancer expressing human PD-1 in transgenic C57BL/6 mice expressing human PD-1 and PD-L1 checkpoint genes [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B81.
Abstract B82: Distinct immune status in patients with adenocarcinoma and squamous cell carcinoma: Implication for immunotherapy of non-small cell lung cancer
Authors: Hradilova Nada , Palata Ondrej , Sadilkova Lenka , Mysikova Dagmar , Mrazkova Hana , Lischke Robert , Spisek Radek , Adkins Irena 
Published: June 2021

Abstract
Lung cancer is the leading cause of cancer mortality worldwide; therefore, understanding the biologic role of immune cell infiltrates in the tumor microenvironment is of eminent interest. In this study we compared immune cell populations, T-cell responses and secreted cytokines in primary tumors and nontumoral lung tissue from more than 40 adenocarcinomas (AC) and 40 squamous cell carcinomas (SCC) of non-small cell lung cancer (NSCLC) patients undergoing neoadjuvant surgery. Moreover, we compared immune-suppressive populations such as CD4+CD25+Foxp3+ T regulatory cells and myeloid-derived suppressor cells (MDSC) and the expression of immune checkpoint molecules PD-1, TIM3, LAG-3 and CTLA-4 in the blood of these patients. In both tumor subtypes we observed similarly higher infiltration of B cells, memory T cells, dendritic cells, NK cells, monocytes/macrophages, mast cells and CD4+CD25+Foxp3+ T regulatory cells compared to nontumoral tissue. However, immune cells seemed to be suppressed functionally more in SCC than AC as we detected significantly lower IFN-γ-positive T cells and production of proinflammatory cytokines after stimulation. PD-1, TIM3 and LAG-3 expression on T cells in blood and PD-1 on intratumoral CD8+ T cells of SSC patients were significantly elevated compared to AC patients. Similarly, the high number of MDSC, which correlated with Arginase 1 mRNA levels and downregulation of CD3zeta in T cells, was detected only in SCC. These results suggest that immune system of SSC patients might be subjected to a higher systemic and tumor-associated immune suppression than in AC patients. This should be taken into consideration in designing lung cancer immunotherapeutic approaches.
Citation Format: Nada Hradilova, Ondrej Palata, Lenka Sadilkova, Dagmar Mysikova, Hana Mrazkova, Robert Lischke, Radek Spisek, Irena Adkins. Distinct immune status in patients with adenocarcinoma and squamous cell carcinoma: Implication for immunotherapy of non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B82.
Abstract B92: Landscape of B-cell immunity and related immune evasion in human cancers
Authors: Hu Xihao Sherlock , Zhang Jian , Liu Jun , Li Bo , Liu Xiaole Shirley 
Published: June 2021

Abstract
Tumor-infiltrating B cell is an important component in the microenvironment with unclear antitumor impacts. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin (Ig) hypervariable regions from bulk tumor RNA-seq data. TRUST assembled over 30 million complementarity-determining region 3 (CDR3s) of the B-cell heavy chain (IgH) from The Cancer Genome Atlas (TCGA). Widespread B-cell clonal expansions and Ig subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations (SCNA) in MICA/B genes related to antibody-dependent cell mediated cytotoxicity (ADCC) were identified in tumors with elevated B-cell activity. IgG3-1 subclass switch interacts with the B cell receptor affinity maturation and defects in the ADCC pathway. The comprehensive pan-cancer analyses of tumor-infiltrating B-cell receptor repertoires revealed novel tumor immune evasion mechanism through genetic alterations. The IgH sequences identified in this work are potentially useful resources for future development of immunotherapies.
Citation Format: Xihao Sherlock Hu, Jian Zhang, Jun Liu, Bo Li, Xiaole Shirley Liu. Landscape of B-cell immunity and related immune evasion in human cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B92.
Abstract IA11: The LXR/ApoE pathway regulates the innate immune system in cancer
Authors: Tavazoie Masoud 
Published: June 2021

Abstract
Harnessing of the adaptive immune system, either by adoptive transfer of engineered T cells or by direct activation of endogenous T cells via checkpoint blockade, has yielded unprecedented clinical benefit in cancer. However, the full potential of these therapies is hampered by a system of elaborate molecular and cellular mechanisms that tumors orchestrate as they evolve to evade T-cell attack during metastatic cancer progression. These mechanisms, collectively referred to as the immune-suppressive tumor microenvironment, rely on cancer co-opting signaling pathways that regulate immunity in noncancer settings, including those implicated in normal physiology or in other disease states. Using an unbiased experimental approach to identify key drivers of cancer metastasis, apolipoprotein E (ApoE) was revealed as a regulator of cancer progression and tumor immunity. As tumors grow and metastasize, ApoE expression becomes silenced via the activity of a group of microRNAs that become switched on during cancer progression. The silencing of ApoE expression in tumors is associated with significantly greater metastatic potential, worse clinical prognosis, and increased accumulation of innate immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). The ApoE pathway has previously been associated with the pathophysiology of atherosclerosis and Alzheimer’s disease, both of which are characterized histologically, in part, by aberrant inflammatory myeloid cell accumulation in the form of myeloid-derived foam cells and myeloid-derived microglia, respectively. In cancer, MDSCs accumulate in tumors and in the circulation, where they inhibit the activity of cytotoxic T cells via the expression of multiple immunosuppressive molecules. Their high abundance in the circulation has been associated with resistance to checkpoint blockade, highlighting their clinical relevance. MDSC abundance was found to be regulated via ApoE signaling through the ApoE receptor LRP8. Therapeutic activation of silenced ApoE expression can be accomplished pharmacologically by the administration of Liver X Receptor (LXR) agonists, which drive ApoE expression transcriptionally. RGX-104, a potent and selective LXR agonist, reversed cancer immune evasion in tumor models and in advanced cancer patients harboring a diverse array of refractory malignancies, including checkpoint inhibitor-refractory cancers. RGX-104 rapidly depleted MDSCs, resulting in restoration of antitumor immunity via activation of PD-1+ CD8+ T cells, which ultimately resulted in clinical antitumor activity.
Citation Format: Masoud Tavazoie. The LXR/ApoE pathway regulates the innate immune system in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA11.
Abstract IA17: Molecular mechanisms of T-cell exhaustion and implications for immunotherapy
Authors: Wherry E. John 
Published: June 2021

Abstract
T-cell exhaustion is common during chronic infections and cancer and prevents optimal immunity. Exhausted CD8 T cells (TEX) are defined by the loss of ability to perform effector functions efficiently, low proliferative capacity, and poor survival following antigen stimulation. TEX also co-express multiple inhibitory receptors that negatively regulate their function. Indeed, receptors such as PD-1 have become major targets of clinical immunotherapies in cancer and infectious disease aimed at reinvigorating TEX. Despite the clinical success of PD-1-based therapies in human melanoma and other cancers, the majority of patients do not have durable clinical benefit from anti-PD-1 monotherapy. A major challenge remains identifying which patients will respond to anti-PD-1 therapy and defining the underlying mechanisms for successful, durable response versus treatment failure. Detailed immune profiling of peripheral blood from stage IV melanoma patients before and after pembrolizumab (pembro) identified reinvigoration in circulating TEX. These data indicated that nearly 80% of patients experienced a strong, on-target immunologic effect of PD-1 blockade. However, the objective clinical response rate in this cohort was less than 40% and reinvigoration of circulating TEX alone did not predict clinical outcomes. We are currently now using neoadjuvant clinical trial designs and preclinical models to dissect the molecular and mechanistic features of effective and ineffective responses to checkpoint blockade and to understand the underlying molecular program of exhausted CD8 T cells. Our emerging data not only provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches, but also point to key underlying molecular pathways involved in programming and controlling the developmental biology of exhausted T cells. The implications of these findings for clinical therapies will be discussed.
Citation Format: E. John Wherry. Molecular mechanisms of T-cell exhaustion and implications for immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA17.
Abstract IA21: From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy
Authors: Sharma Padmanee 
Published: June 2021

Abstract
Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1 and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted presurgical and tissue-based clinical trials, which permit access to tumor tissues for laboratory studies. To compare and contrast data, we chose one tumor type that responds well to immune checkpoint therapy and one that does not. The first presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. The second presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in patients with localized prostate cancer. In addition, we evaluated data from patients with melanoma who received immune checkpoint therapy. These data enabled us to identify the ICOS/ICOSL pathway as relevant for antitumor immune responses in the setting of anti-CTLA-4 therapy. We also identified resistance mechanisms including expression of other immune inhibitory pathways, such as VISTA, and loss of the IFNγ signaling pathway in tumor cells. These data will be discussed in greater details.
Citation Format: Padmanee Sharma. From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA21.
Abstract IA26: Dynamic interactions between myeloid and lymphoid cells regulate response to therapy in solid tumors
Authors: Coussens Lisa M. 
Published: June 2021

Abstract
The concept that leukocytes are critical components of solid tumors is now generally accepted; however, their role(s) in regulating aspects of neoplastic progression, and/or response to cytotoxic, targeted, and/or immune therapy is only beginning to be understood. Utilizing de novo mouse models of organ-specific solid tumor development (mammary, cutaneous, and pancreas carcinomas and mesothelioma), we now appreciate that adaptive leukocytes differentially regulate myeloid cell recruitment, activation, and effector function, and in turn, activated tumor-infiltrating myeloid cells engage tissue-based programs to foster malignancy and repress antitumor immunity by a diversity of mechanisms. Treatment of tumor-bearing mice with therapeutic agents that disrupt lymphocyte-myeloid cell interaction, myeloid cell activation, or myeloid cell functionality generally slows primary tumor growth kinetics when combined with cytotoxic therapy; however, their impact on metastases is variable. Similar to organ-specific regulatory programs co-opted to foster primary tumor growth, regulation of metastatic seeding and outgrowth is also regulated by tissue- and organ-specific mechanisms. Based on this, it stands to reason that therapeutic strategies may not be efficacious in both primary and metastatic locations. To be presented will be our recent insights into organ- and tissue-specific regulation of primary and metastatic cancer development by adaptive and innate immune cells, how systemic regulation of humoral immunity and complement-mediated pathways regulate pro- versus antitumor immune responses, and new studies evaluating how attenuating protumor properties of select lymphoid and myeloid cells can be exploited to enhance therapeutic responses to cytotoxic and immune-based therapy.
LMC acknowledges generous support from the NIH/NCI, the Department of Defense Breast Cancer Research Program Era of Hope Scholar Expansion Award, Susan G. Komen Foundation, the Breast Cancer Research Foundation, the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant.
Citation Format: Lisa M. Coussens. Dynamic interactions between myeloid and lymphoid cells regulate response to therapy in solid tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA26.
Abstract PR08: Discovery of immune regulators in primary human T cells using genome-wide CRISPR screens
Authors: Carnevale Julia , Shifrut Eric , Tobin Victoria , Roth Theodore , Woo Jonathan , Bui Christina , Li Jonathan , Diolaiti Morgan , Ashworth Alan , Marson Alexander 
Published: June 2021

Abstract
The incredible success of cancer immunotherapies is still only limited to subsets of patients, which has motivated efforts to discover novel therapeutic targets to boost tumor killing by effector T cells. However, the translational potential of these discoveries may be limited by suboptimal correlation between cell line and animal models with human disease. Further, the majority of unbiased screening approaches are performed in cancer cells lines, rather than in the effector T cells themselves. We have developed a novel and flexible screening platform using sgRNA lentiviral infection with Cas9 protein electroporation (SLICE), to perform genome-wide CRISPR screens in primary human T cells at genome-wide scale. We have used this platform to survey the response of primary human CD8+ T cells to TCR stimulation. This screen revealed essential components of TCR signaling and inhibitors/agonists of T-cell proliferation. Targeted deletion of top candidate genes from the screen led to increased proliferation, increased expression of activation markers, and improved tumor killing in in vitro co-culture models. Coupling our screening platform with single-cell RNA-seq identified functional clustering of cell states across perturbations and showed that pooled screens in primary cells can now be analyzed at a single-cell level. In addition to finding ways to boost intrinsic T-cell activation, we also sought to adapt the SLICE screening platform to identify mediators of resistance to immunosuppressive forces in the tumor microenvironment. To model one such suppressive factor, we performed the screen in the presence of a potent adenosine agonist and found known and novel regulators of adenosine signaling in T cells. We are further integrating this platform with a two-cell co-culture system to attempt to find mechanisms of resistance to immunosuppressive cells in the tumor microenvironment. This novel platform provides the framework for unbiased, large-scale discovery of immune regulators as potential therapeutic targets in primary human T cells.
This abstract is also being presented as Poster A90.
Citation Format: Julia Carnevale, Eric Shifrut, Victoria Tobin, Theodore Roth, Jonathan Woo, Christina Bui, Jonathan Li, Morgan Diolaiti, Alan Ashworth, Alexander Marson. Discovery of immune regulators in primary human T cells using genome-wide CRISPR screens [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR08.
Abstract PR11: Tumor cell-intrinsic factors underlie the heterogeneity of immune infiltration and response to immunotherapy in pancreatic cancer
Authors: Li Jinyang , Byrne Katelyn T. , Yan Fangxue , Yamazoe Taiji , Chen Zeyu , Baslan Timour , Richman Lee P. , Lin Jeffrey , Sun Yu H. , Liudahl Shannon M. , Tobias John W. , Lowe Scott , Coussens Lisa M. , Wherry John E , Vonderheide Robert H. , Stanger Ben Z. 
Published: June 2021

Abstract
Intertumoral heterogeneity—the biologic and functional differences among different individual tumors—poses a challenge for immunotherapy. To understand the tumor cell-intrinsic factors underlying the heterogeneity of tumor immunity and sensitivity to immunotherapy, we established a new experimental system by generating a library of congenic pancreatic tumor cell clones from a genetic mouse model driven by mutant Kras and p53. These tumor cell clones robustly formed implanted tumors that recapitulated the T cell-inflamed and non-T cell-inflamed tumor microenvironments in human patients, associated with distinct patterns of infiltration by T cells and myeloid cells. We found that the non-T cell-inflamed phenotype was dominant over the T cell-inflamed phenotype in the local tumor microenvironment. Both quantitative and qualitative features, specifically expression of markers of prior TCR activation, of intratumoral CD8+ T cells predicted the response to immunotherapies. An integrated transcriptomic and epigenetic analysis revealed that tumor cell-intrinsic expression of the chemokine CXCL1 as a major determinant of the non-T cell-inflamed microenvironment, and ablation of tumor cell-intrinsic CXCL1, promoted T-cell infiltration and sensitivity to a combination of chemotherapies, CD40 agonist, and checkpoint blockades. These results demonstrated that heterogeneity of tumor immune phenotypes is driven by tumor cell-intrinsic factors that can be manipulated to influence the outcome of immunotherapies. The observation that non-T cell-inflamed phenotype is dominant emphasized the importance of targeting mechanisms driving T-cell low phenotype for improving immunotherapy response. This experimental system will provide opportunities for understanding other aspects of tumor heterogeneity as well.
This abstract is also being presented as Poster A45.
Citation Format: Jinyang Li, Katelyn T. Byrne, Fangxue Yan, Taiji Yamazoe, Zeyu Chen, Timour Baslan, Lee P. Richman, Jeffrey Lin, Yu H. Sun, Shannon M. Liudahl, John W. Tobias, Scott Lowe, Lisa M. Coussens, John E Wherry, Robert H. Vonderheide, Ben Z. Stanger. Tumor cell-intrinsic factors underlie the heterogeneity of immune infiltration and response to immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR11.