bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A38: Targeting the androgen receptor to increase sensitivity to checkpoint immunotherapy
Authors: Sehrawat Archana , Polesso Fanny , Hipfinger Christina , Guan Xiangnan , Xia Zheng , Graff Julie , Moran Amy 
Published: March 2020

Abstract
Advanced prostate cancer is the second leading cause of cancer-associated mortality in men with ~32,000 deaths each year. Castration-resistant prostate cancer has no cure and an overall survival of approximately 5 years. Strategies to block androgen receptor (AR) signaling form the backbone of prostate-cancer therapy and despite suppression of serum testosterone, intratumor concentrations of androgens can remain high. Blocking AR nuclear translocation and its transcriptional function delays disease progression, but not overall survival, in castration-resistant prostate cancer patients. In a paradigm-challenging clinical trial, anti-PD-1 blockade induced long-term durable responses in a subset of metastatic castration-resistant prostate cancer patients treated with the AR inhibitor, enzalutamide. Interestingly, T cells also express AR and their function can be directly modulated by changes in androgen availability. Given this and the success of this clinical trial, we asked if enzalutamide sensitized T cells to checkpoint immunotherapy. Using in vitro and in vivo assays, we reveal a direct effect of enzalutamide on T-cell proliferation and function. In a novel implantable mouse model of advanced prostate cancer, we highlight a requirement for androgen receptor blockade to sensitize prostate tumor-bearing animals to immunotherapy. Transcriptomic analysis of leukocytes from the tumor and draining lymph node revealed a small cohort of genes differentially regulated by enzalutamide that are consistent with increased sensitivity to checkpoint blockade. Perhaps most significant, in patients who responded to anti-PD-1 therapy, some of these same genes were upregulated prior to treatment, suggesting these could be a biomarker for immunotherapy sensitization in advanced prostate cancer patients. Taken together, our data suggest a novel mechanism targeting androgen receptor-mediated immune suppression to improve immunotherapy outcomes in advanced prostate cancer.
Note:This abstract was not presented at the conference.
Citation Format: Archana Sehrawat, Fanny Polesso, Christina Hipfinger, Xiangnan Guan, Zheng Xia, Julie Graff, Amy Moran. Targeting the androgen receptor to increase sensitivity to checkpoint 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 A38.
Abstract A41: Absence of central tolerance as a sculpting mechanism of immune-checkpoint therapy
Authors: Benitez Asiel A. , Khalil-Aguero Sara , Nandakumar Anjali , Gupta Namita , Zhang Wendy , Atwal Gurinder S. , Murphy Andrew J. , Sleeman Matthew A. , Haxhinasto Sokol 
Published: March 2020

Abstract
Therapeutic targeting of immune checkpoint pathways, which are exploited by tumors to evade the immune system, can result in increased overall survival for some patients with specific types of cancers. The endogenous antitumor response is limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring their deletion to protect against autoimmunity. In this study, we show that compared to wild-type mice, tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models and was accompanied by increased numbers of activated T cells expressing high levels of genes such as Gzma, Gzmb, Perforin, and Cxcr3, and tumors contained high levels of the chemokines Cxcl9 and Cxcl10 compared to wild-type mice. Furthermore, there was an enrichment of T cells expressing markers associated with the potent antitumor tissue-resident memory T cells expressing Cd103. Consistent with Aire’s central role in T cells’ repertoire selection, single-cell TCR sequencing unveiled the expansion of several clones with high tumor reactivity. Together, these results show that a break in central tolerance in combination with immune checkpoint blockade can potently enhance antitumor immunity and serve as a model system to unmask novel antitumor therapies.
Citation Format: Asiel A. Benitez, Sara Khalil-Aguero, Anjali Nandakumar, Namita Gupta, Wendy Zhang, Gurinder S. Atwal, Andrew J. Murphy, Matthew A. Sleeman, Sokol Haxhinasto. Absence of central tolerance as a sculpting mechanism of immune-checkpoint 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 A41.
Abstract A47: scRNA-seq reveals functionally distinct gd T cells in human colorectal tumors
Authors: Harmon Cathal , Zaborowski Alex , Kane Harry , Cunningham Stephen , Agudelo Leandro , Kellis Manolis , Winter Des , Lynch Lydia 
Published: March 2020

Abstract
Colorectal cancer is the third most common malignancy worldwide, with increasing numbers due to the spreading obesity epidemic and Western diet. Colorectal tumors are subclassed by mutational burden, caused by microsatellite instability (MSI). MSI-high tumors tend to induce robust T-cell responses and respond well to immunotherapy. However, microsatellite-stable (MSS) tumors lack high mutational burden and conventional T-cell recognition. While these tumors have therefore been considered immunologically “cold,”, MSS tumors are infiltrated by innate lymphocytes, including gd T cells, natural killer (NK) cells, and mucosal associated invariant T (MAIT) cells. We therefore focused on the innate antitumor response in these patients. Colon tumor and uninvolved tissue were sampled from 6 patients undergoing surgical resection for MSS tumors. Using the 10x genomics platform, single-cell RNAseq was performed on isolated populations of gd T cells, NK cells, MAIT cells, and conventional T cells. Single-cell analysis of these tumors revealed significant heterogeneity in all cell subsets analyzed, revealing phenotypic and functional changes not previously observed in bulk sequencing data. A subset of gdT cells adopted a wound healing phenotype in all colorectal cancer samples. These soluble factors are involved in the tissue repair response and barrier integrity, providing mitogenic signals to epithelial cells. In addition, they are associated with immune suppression and induction of regulatory T cells. In humans, this phenotype can be induced in Vd1 T cells in response to proinflammatory cytokine stimulation. In the murine gut, resident gd T cells adopt this phenotype basally and increase production in response to inflammatory cytokine production. The combination of pro-tissue growth and immune suppression, by gd T cells, likely contributes to the poor immunogenicity of MSS tumors. Depleting or converting these cells represents a novel immunotherapeutic target in colorectal cancer.
Citation Format: Cathal Harmon, Alex Zaborowski, Harry Kane, Stephen Cunningham, Leandro Agudelo, Manolis Kellis, Des Winter, Lydia Lynch. scRNA-seq reveals functionally distinct gd T cells in human colorectal tumors [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 A47.
Abstract A49: Acquired resistance of non-small cell lung cancer to EGFR-TKI: Role of AKT3
Authors: Huang Shih-Hsiang , Shih Jin-Yuan , Chen Ching-Chow 
Published: March 2020

Abstract
The discovery of EGFR-TKIs has had a dramatic impact on the treatment of NSCLC with EGFR activation mutation. Although they improve the overall survival, the main obstacle is the emergence of acquired resistance. Two resistant cells, HCC827/IR (IRESSA resistance) and H1975/AR (AZD9291 resistance), generated and showing “off-target resistance,” were employed to investigate the molecular and cellular characteristics of the acquired resistance to EGFR-TKIs. AKT activation (p-AKT) in both parental cells was more sensitive to EGFR-TKIs than that in resistant cells. We found that mRNA and protein of AKT3, but not AKT1 and AKT2, were upregulated in both HCC827/IR and H1975/AR cells. Immunoprecipitation of AKT3 demonstrated its contribution to AKT activation. Knockdown of AKT3 in both resistant cells decreased basal AKT activation (p-AKT). However, the insensitive inhibition of gefitinib on AKT activation (p-AKT) in HCC827/IR cells and AZD9291in H1975/AR cells remained even if AKT3 was knocked down. AKT3 protein, but not AKT1 and AKT2, was found to be overexpressed in resistant cells treated with gefitinib or AZD9291 as well as AKT3 KD, indicating the crucial role of AKT3 in acquired resistance to EGFR-TKIs. Combination of AKT inhibitors with AZD9291 showed synergistic inhibition on cell viability of H1975/AR cells. Therefore, AKT3 upregulation might be one of the mechanisms for acquired resistance to EGFR-TKIs, and it might serve as a predictive biomarker for EGFR-TKIs therapy.
Citation Format: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen. Acquired resistance of non-small cell lung cancer to EGFR-TKI: Role of AKT3 [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 A49.
Abstract A71: Chitinase-3-like-1: A new immunomodulatory target in lung cancer
Authors: Akosman Bedia , Ma Bing , Kamle Suchitra , Kurtulus Dilara , Lee Chang-Min , Lee Chun , Elias Jack 
Published: March 2020

Abstract
One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint molecules (ICPs) such as PD-1 and its ligands PD-L1 and PD-L2 as an immune evasion mechanism for cancer cells. Although the immunotherapeutics targeting ICPs have great success in many tumors, including lung cancer, still the response rates are very limited. Thus, understanding the underlying regulatory mechanism for these molecules is essential to develop rational and new immunotherapeutic strategies to maximize the clinical outcomes for patients. Chitinase 3-like-1, as a proinflammatory and protumorigenic molecule, has increased expression in many solid tumors including lung cancer. Circulating levels of Chi3l1 are also highly correlated with poor prognosis and decreased survival rates. However, the specific role of Chi3l1 in tumor initiation and progression and as an immunomodulator in the pulmonary tumor microenvironment has not been adequately defined. Recently we have discovered that melanoma lung metastasis was significantly reduced in Chi3l1 null mutant (Brp39−/−) mice and the mice treated with anti-Chi3l1 antibody (FRG) while it was increased in overexpressing transgenic mice (YKL-40 Tg) compared to the controls, suggesting a critical role of Chi3l1 in metastatic spread and colonization. We also showed that Chi3l1 transgene expression leads to infiltration of immune cells, particularly myeloid cells into the lung, and causes dysregulated expression of PD-L1 on the macrophages. In vitro studies by using bone marrow-derived macrophages demonstrated a blunted IFNg induced PD-L1 expressions in Brp39−/− cells compared to WT controls. Additionally, we have found that the FRG antibody has synergizing effect on anti-PD1 treatment in metastatic lung cancer model. FRG antibody treatment can also effectively inhibit tumor development and also promotes CD8+ T-cell infiltration into the tumor area compared to control treatment in primary lung cancer model (K-ras+/G12D/ P53−/−mice). Overall, our studies demonstrated that Chi3l1 plays an important role in lung cancer development or progression through regulating PD-1/PD-L1/L2 axis and T-cell infiltration. These studies also highlight a significant therapeutic potential of FRG antibody for lung cancer as a single or combinational immunotherapeutic agent.
Citation Format: Bedia Akosman, Bing Ma, Suchitra Kamle, Dilara Kurtulus, Chang-Min Lee, Chun Lee, Jack Elias. Chitinase-3-like-1: A new immunomodulatory target in lung cancer [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 A71.
Abstract A73: Fucosylation in CD4+ T cell-mediated melanoma suppression
Authors: Lester Daniel K. , Innamarato Pasquale , Kodumudi Krithika , Watson Gregory , Mercurio Matt , Pilon-Thomas Shari , Messina Jane , McCarthy Susan , Lau Eric 
Published: March 2020

Abstract
While immunotherapies have had a striking efficacy in melanoma patients, significant proportions of melanoma patients exhibit poor responsiveness to immunotherapies. Further understanding of immunoregulatory mechanisms is needed to improve immunotherapies. Previously, we discovered increasing tumor fucosylation in melanomas reduces tumor growth and metastasis (Lau et al., 2015). To identify tumor-infiltrating lymphocytes (TILs) affected by L-fucose, we profiled lymphocytes from syngeneic tumors of control- or fucose-fed mice tumors. Dietary supplementation of L-fucose increased TILs by ~10-50-fold. Of total TILs, CD3+ T cells (including CD4+ and CD8+ T cells) doubled. L-fucose did not trigger tumor suppression in immune-deficient mouse melanoma models, indicating the immune system’s requirement for L-fucose-triggered suppression. Immunodepletion of CD4+ or CD8+ T cells during L-fucose treatment revealed that CD4+ T cells are crucial for tumor suppression. CD4+ T-cell depletion abrogated infiltration of NK, dendritic, and CD8+ T cells in the tumors, implicating these populations as downstream effectors of fucosylation- and CD4+ T cell-triggered tumor suppression. To identify proteins on melanomas contributing to fucosylation-triggered immune responses, we performed mass spectrometric analysis of all fucosylated proteins in melanoma and identified 2 MHC proteins, HLA-A and HLA-DRB1, as fucosylated. Knockdown of HLA- DRB1 and HLA-A in vivo revealed HLA-DRB1 is required for L-fucose-mediated tumor suppression, and notably, for recruitment of CD4+ T cells. We further investigated how fucosylation affects CD4+ T-cell biology using CD4+ T cells isolated from healthy donors, which we pharmacologically modulated fucosylation. The roles of fucosylation on tumor vs. CD4+ T cells and clinical utility/implications for melanoma patients will be discussed. Our data show how increased fucosylation drives tumor suppression through CD4+ T cells, and support the potential of dietary L-fucose to boost immunity in melanomas.
Citation Format: Daniel K. Lester, Pasquale Innamarato, Krithika Kodumudi, Gregory Watson, Matt Mercurio, Shari Pilon-Thomas, Jane Messina, Susan McCarthy, Eric Lau. Fucosylation in CD4+ T cell-mediated melanoma suppression [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 A73.
Abstract A79: Inhibition of p53-MDM2 protein interaction reduces tumor growth in a mouse melanoma model
Authors: Ingelshed Katrine , Lianoudaki Danai , Lama Dilraj , Sohn Silke , Fritz Nicolas , Jiang Long , Wermeling Fredrik , Karlsson Mikael , Lane David P. , Sedimbi Saikiran K. 
Published: March 2020

Abstract
Tumor suppressor protein p53 is mutated in close to 50% of human tumors. Under steady state conditions, the two E3 ligases MDM2 and MDM4 interact with and inhibit the transcriptional activity of p53. Inhibition of p53-MDM2/4 interaction to reactivate p53 has therefore been considered a therapeutic strategy. In this study, we tested p53-MDM2 protein-protein interaction inhibition using the small molecule AMG 232, which is currently being tested in phase 1b/2a clinical trials. In vitro, AMG 232 induced a significant, p53-dependent growth arrest in the mouse melanoma cell line B16-F10. Using mass spectrometry-based proteomics, we identified differential protein expression patterns following AMG 232 treatment of B16-F10 melanoma cells. In vivo, the growth of B16-F10 melanoma cells implanted in WT C57BL/6 mice was significantly reduced by AMG 232 treatment. Our data demonstrate that AMG 232 induces a p53-dependent tumor growth arrest in an immunocompetent mouse model, and we are currently testing whether AMG232 can synergize with checkpoint immunotherapy.
Citation Format: Katrine Ingelshed, Danai Lianoudaki, Dilraj Lama, Silke Sohn, Nicolas Fritz, Long Jiang, Fredrik Wermeling, Mikael Karlsson, David P. Lane, Saikiran K. Sedimbi. Inhibition of p53-MDM2 protein interaction reduces tumor growth in a mouse melanoma model [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 A79.
Abstract A89: Microglial galectin-3 enhances the metastatic phenotype of breast cancer cells in brain metastases
Authors: Kersch Cymon N. , Morris DreeAnna F. , Muldoon Leslie L. , Neuwelt Edward A. 
Published: March 2020

Abstract
Background: Breast cancer brain metastases have poor prognosis and few treatment options. When breast cancer cells invade the brain, they interact with the vasculature and resident brain cells, including microglia and astrocytes. We hypothesize that brain cells produce factors that enhance the growth and invasion of breast cancer cells in the brain.
Methods: Human breast cancer cell lines (MDA-MB231BR-HER2 and HCC1954) were inoculated intracranially in athymic rats as xenograft models of brain metastasis. Brains were analyzed for protumorigenic factor expression in the tumor microenvironment using fluorescent immunohistochemistry. In vitro assays assessed factors involved in breast cancer cell proliferation, morphology, and migration.
Results: The brain tumor xenografts showed infiltration into the perivascular space. Galectin-3 (Gal3) colocalized with reactive microglia in and around the tumors. In vitro, Gal3 increased HCC1954 cell proliferation and migration. In transwell coculture assays, BV2 microglial cells increased the migration of HCC1954 breast cancer cells &gt;25 fold, which was prevented by cilengitide, an inhibitor of alpha(v)beta(3)-integrin cell adhesion protein. ELISA analysis demonstrated that BV2 microglia secrete Gal3 in the presence of HCC1954 cells. Gal3 is known to bind and induce clustering of alpha(v)beta(3)-integrin, which is expressed on metastatic breast cancer cells. Immunohistochemistry of clinical specimens revealed that Gal3 is expressed in/around human breast cancer brain metastases.
Conclusions: These data suggest that factors produced in the tumor microenvironment promote the growth and migration of breast cancer cells in the brain. Gal3, produced and secreted by activated microglia in vitro and expressed in and around brain metastases, increases the invasive capability of breast cancer cells. The interactions of neoplastic cells with the brain environment may provide a target to improve therapy of brain metastases.
Citation Format: Cymon N. Kersch, DreeAnna F. Morris, Leslie L. Muldoon, Edward A. Neuwelt. Microglial galectin-3 enhances the metastatic phenotype of breast cancer cells in brain metastases [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 A89.
Abstract A9: Systemic immune response profiling with SYLARAS implicates a role for CD45R/B220+ CD8+ T cells in glioblastoma immunology
Authors: Baker Gregory J. , Palaniappan Sucheendra K. , Moore Jodene K. , Davis Stephanie H. , Santagata Sandro , Sorger Peter K. 
Published: March 2020

Abstract
Research tools for the rapid and accurate assessment of bulky single-cell datasets are needed to achieve a more integrated comprehension of immune response to disease and therapy. Here we describe SYLARAS (Systemic Lymphoid Architecture Response Assessment), a modular and extensible research platform for the acquisition, statistical analysis, and visual display of multi-organ immune response data. Leveraging our technology against a syngeneic mouse model of glioblastoma (GBM), we reveal the tumor’s influence on immune cell subsets hitherto undescribed in the disease, including CD45R/B220+ CD8+ T cells characterized by their ability to constrain immune response to autologous antigens. Ancillary studies show that these cells are transcriptionally and morphologically distinguishable from conventional CD8+ T lymphocytes and infiltrate the brain tumor microenvironment of rodents and humans. The ability of SYLARAS to provide ample content on the cell and molecular mechanisms governing systemic immune response makes it a broadly useful preclinical research tool in the era of immunotherapy.
Citation Format: Gregory J. Baker, Sucheendra K. Palaniappan, Jodene K. Moore, Stephanie H. Davis, Sandro Santagata, Peter K. Sorger. Systemic immune response profiling with SYLARAS implicates a role for CD45R/B220+ CD8+ T cells in glioblastoma immunology [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 A9.
Abstract B10: Novel CRISPR/Cas9 vectors for in vivo tumor functional genomics
Authors: Dubrot Juan , Manguso Robert T. , Lane-Reticker Sarah Kate , Ayer Austin , Kessler Emily , Wolfe Clara , Mahapatra Animesh 
Published: March 2020

Abstract
During the last decade, there has been notable progress in cancer immunotherapy, including promising clinical success of immune checkpoint inhibitors. Moreover, there is an increasing number of new potential targets for cancer immunotherapy that are currently being developed both as monotherapy or in combination. However, the lack of durable clinical responses due in part to the resistance mechanisms that tumors exhibit in a significant proportion of patients urges novel approaches to find the right therapeutic strategies. The understanding of such tumor evasion mechanisms and the complex interactions that take place in the tumor microenvironment is essential to obtain successful treatments. Functional genomics has emerged as a powerful tool that can help to reveal some of these unknown processes, with CRISPR-Cas9 technology the most prominent example. However, in vivo genetic screens require stable expression of several components that in most cases are not derived from murine cells, which represents a major obstacle in the context of cancer immunology. The inoculation of engineered tumor cell lines in immunocompetent mice results in either tumor rejection or an aberrant response to immunotherapy, making the experiments technically impossible in the first case or providing inconsistent results in the latter. We have designed new vector strategies to overcome the altered immunogenicity of Cas9-expressing tumor cell lines using the Cre-lox system. Expression and effective removal of Cas9 and vector components are monitored using fluorescent reporter proteins. Both genome-editing capacity and normal in vivo behavior of all tested cell lines remain largely unaltered using this novel strategy. This technology represents a major advance for preclinical functional genomics, allowing studies in fully competent animals looking for better combination treatments and resistance mechanism in particular cancer models, and ultimately will help in the design of clinical trials.
Citation Format: Juan Dubrot, Robert T. Manguso, Sarah Kate Lane-Reticker, Austin Ayer, Emily Kessler, Clara Wolfe, Animesh Mahapatra. Novel CRISPR/Cas9 vectors for in vivo tumor functional genomics [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 B10.