bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL-20/IL24-IL20RA axis
Authors: Li Jia , Qin Xuan , Xu Mengyao , Yan Jie , Wang Longlong , Shi Yi , Xiang Rong 
Published: March 2020

Abstract
Ovarian cancer has high mortality among all gynecologic malignancies due to the lack of clear symptoms at early stage and the metastasis of cancer cells when diagnosed with advanced stages. The disseminated ovarian cancer cells have to overcome the immune surveillance in abdominal environment, which is rich in many types of immune cells, to survive and proliferate. However, the key genes and mechanisms preventing the metastasis of ovarian cancer cells into abdominal sites remain largely unexplored. Here, through an in vivo, genome-scale CRISPR/Cas9 knockout screening, we identified IL-20/IL24-IL20RA as a key checkpoint preventing the abdominal metastasis of ovarian cancer cells. In ovarian cancer patients, the level of IL20RA is dramatically decreased in metastatic cancer cells when compared with that in primary sites. Overexpression of IL20RA in highly metastatic ovarian cancer cells greatly suppressed the abdominal metastasis of ovarian cancer and the formation of ascites. In contrast, silencing IL20RA could increase the metastasis of ovarian cancer cells. We further examined IL02RA-mediated crosstalk between the disseminated cancer cells and the immuno-microenvironment in mouse in vivo ovarian cancer models and in vitro coculture experiments. Silencing IL20RA in ovarian cancer cells resulted in a dramatic decrease of M1 subtype of macrophages and increase of the M2 subtype of macrophages without affecting the population of T and B lymphocytes in ascites. Further mechanistic studies revealed that the ovarian cancer cells, when invaded into the abdominal sites, greatly induced the mesothelial cells in peritoneum to produce IL20RA ligands, i.e., IL-20 and IL-24, which in turn activated the IL20RA downstream signaling in ovarian cancer cells to trigger the production and maturation of IL-18. IL-18, when secreted into the microenvironment, was able to promote the polarization of macrophages into M1-subtype to clear the cancer cells. Thus, we identified a novel immune checkpoint IL20/IL24-IL20RA that was always downregulated in metastatic ovarian cancer cells to prevent the formation of an antitumor immune microenvironment, which could be utilized to develop new strategies for the immunotherapy of ovarian cancers.
Citation Format: Jia Li, Xuan Qin, Mengyao Xu, Jie Yan, Longlong Wang, Yi Shi, Rong Xiang. The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL-20/IL24-IL20RA axis [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 B52.
Abstract B56: YAP1 inhibits host cell immunity and increases human papillomavirus (HPV) infection to drive cervical tumorigenesis
Authors: Lv Xiangmin , He Chunbo , Huang Cong , Wang Hongbo , Chen Li , Chen Peichao , DavisS John S. , Rueda Bo R. , Wang Cheng 
Published: March 2020

Abstract
Although human papillomavirus (HPV) is believed to be the major causative agent for cervical cancer, accumulating evidence indicates that HPV alone is insufficient to induce cervical cancer. The molecular mechanisms underlying cervical cancer development remain unclear. In the present study, we provide evidence showing that the Hippo/YAP pathway plays a critical role in cervical carcinogenesis. We found that genetic alteration of the Hippo/YAP pathway frequently occurred in human cervical cancer patients and was associated with poor prognosis of these patients. Keratin 14 promoter-driven expression of constitutively active YAP1 (YAP S127A) in mouse cervical epithelial cells induced invasive cervical squamous cell carcinoma (CVSCC), suggesting that hyperactivation of YAP1 is sufficient to induce cervical cancer. Importantly, hyperactivation of YAP1 in cervical epithelial cells not only increased the putative HPV receptor molecules and cellular susceptibility to HPV infection, but also disrupted the host cell innate immune system, resulting in failure of HPV viral recognition, suppression of type I IFN production, inhibition of the IFNRs/JAKs/STATs pathway, and blockage of production of antiviral interferon-stimulated genes. Cervical epithelial-specific YAP1 and HPV double knockin mouse models showed that YAP1 synergizes with HPV to promote the initiation and progression of CVSCC. The present study demonstrates that the Hippo/YAP pathway plays a central role in the development of CVSCC and the synergism between hyperactivated YAP1 and high-risk HPV may be the key driver of cervical cancer development. The Hippo/YAP signaling pathway may represent a promising target for developing novel strategies to prevent and treat cervical cancer.
Citation Format: Xiangmin Lv, Chunbo He, Cong Huang, Hongbo Wang, Li Chen, Peichao Chen, John S. DavisS, Bo R. Rueda, Cheng Wang. YAP1 inhibits host cell immunity and increases human papillomavirus (HPV) infection to drive cervical tumorigenesis [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 B56.
Abstract B58: Gasdermin E suppresses tumor growth by activating antitumor immunity
Authors: Zhang Zhibin , Zhang Ying , Xia Shiyu , Kong Qing , Li Shunying , Liu Xing , Junqueira Caroline , Ansara James , Sengupta Satyaki , Yao Yandan , Wu Hao , Lieberman Judy 
Published: March 2020

Abstract
The gasdermins (GSDM) are a family of homologous pore-forming proteins that cause pyroptosis, an inflammatory death associated with loss of cell membrane integrity and release of inflammatory mediators. Gasdermin E (GSDME, also known as DFNA5) as the most ancient member of the GSDM family has been implicated as a tumor suppressor. GSDME is epigenetically inactivated by promoter DNA methylation in a number of cancers and mutated in some other cancers. Worse 5-year survival and an increase in lymph node metastases are associated with reduced GSDME in breast cancer. During classic apoptosis, caspase-3 activates GSDME by cleaving after Asp270. GSDME activation converts noninflammatory apoptotic death to an inflammatory pyroptotic death. This switch could have a profound effect on the ability of tumor cells to survive intrinsic cellular stresses and extrinsic challenges, such as ER stress, chemotherapy drugs, or immune attack by cytotoxic lymphocytes. Here we show reduced GSDME function of 7 of 8 tested cancer-associated mutations. By manipulating GSDME expression in diverse cancer cell lines, we show that Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme-repressed tumors inhibits, tumor growth. Our data demonstrate that GSDME tumor-suppressive effect is cell-extrinsic, mediated by cytotoxic lymphocyte killing and abrogated in perforin-deficient mice or mice lacking lymphocytes. Tumor suppression depended on GSDME’s ability to form cell membrane pores that cause inflammatory pyroptosis, since it was completely blocked by mutating the GSDME cleavage site for pore formation. Using different cancer models, we further show that GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK and CD8+ T lymphocytes. Importantly, we identify that immune killer cells could activate GSDME-mediated pyroptosis independently of caspase activation, when killer cell cytotoxic protease granzyme B directly cleaves and activates GSDME at the same site as caspase-3 (Asp270). Therefore, immune killer cells induce pyroptosis in target GSDME-expressing cancer cells, creating an inflammatory tumor microenvironment that further facilities immune cell tumor infiltration and forms a positive feedback loop. Thus, GSDME suppresses tumor growth by activating antitumor immunity.
Citation Format: Zhibin Zhang, Ying Zhang, Shiyu Xia, Qing Kong, Shunying Li, Xing Liu, Caroline Junqueira, James Ansara, Satyaki Sengupta, Yandan Yao, Hao Wu, Judy Lieberman. Gasdermin E suppresses tumor growth by activating 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 B58.
Abstract B62: Development of novel chimeric antigen receptor T cells for immunotherapy of hepatocellular carcinoma
Authors: Jiang Xiaotao , Caraballo G. Leidy D. , Zhang Huajun , Chi Xiangyang , Peng Yibing , He Aiwu R. , Shao Yanxia , Cai Lun , He Yukai 
Published: March 2020

Abstract
Background and Aim: Several glypican 3 (hGPC3)-specific chimeric-antigen-receptor modified T cells (CARTs) are in trials for hepatocellular carcinoma (HCC), but most are constructed from one monoclonal antibody (mAb). It is unknown how targeting different hGPC3 epitopes will affect CART’s efficacy. The aim of this study is to develop novel effective CARTs by targeting different regions of hGPC3.
Methods: BalB/C mice were immunized with hGPC3 protein to generate novel mAbs that targeted different regions of hGPC3. CARTs were then built from mAbs and their antitumor effect was studied.
Results: Twenty-two mAbs were identified by ELISA. Fourteen of them bound HepG2 cells. Five mAbs were further characterized by immunohistochemical staining. Three of them (6G11, 8F8, and 12D7) were found to specifically stain HCC tumors but not adjacent normal tissues. The mAbs’ affinity was in the nanomolar range. 6G11 and 8F8 bound to hGPC3 N-(AA25-39) and C-(AA463-496) epitopes, respectively. 12D7 recognized a conformational epitope in the hGPC3 N-fragment (AA25-358). All CARTs built from the mAbs underwent expansion after GPC3+ cell stimulation. However, their effector function was significantly different. 8F8 CARTs possessed the strongest effector function. 6G11 CARTs experienced the greatest expansion, but with slightly weaker function. In contrast, 12D7 CARTs showed minimal effector function. Soluble hGPC3 did not activate CARTs or block CART activation by tumor cells. Adoptive transfer of 8F8 and 6G11, but not 12D7, CARTs generated complete regression of HCC xenografts in NSG mice.
Conclusion: The three novel CARTs that target a membrane-distal N-epitope, a membrane-proximal C-epitope, or a conformational epitope of hGPC3 possessed different effector function and antitumor effects. CARTs targeting the hGPC3 N- or C specific epitope generated potent antitumor effects, while CARTs targeting an hGPC3-N conformational epitope showed minimal effector function.
Citation Format: Xiaotao Jiang, Leidy D. Caraballo G., Huajun Zhang, Xiangyang Chi, Yibing Peng, Aiwu R. He, Yanxia Shao, Lun Cai, Yukai He. Development of novel chimeric antigen receptor T cells for immunotherapy of hepatocellular carcinoma [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 B62.
Abstract B72: Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cell-based immunotherapy
Authors: Yao Li-Chin , Cheng Mingshan , Shultz Leonard D. , Greiner Dale L. , Brehm Michael A. , Keck James G. 
Published: March 2020

Abstract
The JAX® Onco-Hu® platform utilizes humanized mice engrafted with tumors to enable in vivo investigation of the interactions between the human immune system and human cancer. We have shown that humanized NOD-scid IL2Rγ null (NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of checkpoint inhibitors. A major avenue of our investigation is to generate humanized mouse models containing a more complete human hematopoietic system and robust innate immune cell population. Nature killer (NK) cells are important players of innate defense against cancerous cells by a number of mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC). To overcome limited NK cell development in humanized NSG mice, we have developed NSG-Tg(Hu-IL15) (JAX stock number 030890) mice constitutively expressing human IL15. Following HSC-engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of human CD16+CD56+ NK cells are detectable as compared to NSG mice in peripheral blood during the whole course of the study (18 weeks). Levels of circulating human CD45+ cells, CD3+ T cells, CD19+ B cells, and CD33+ myeloid cells are similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Previously we have described that the human NK cells developing in HSC-engrafted NSG-Tg(Hu-IL15) mice are functional and can lyse the NK-sensitive target cells K562 by in vitro cytotoxicity assay. We also showed that NK cells limit the growth of a PDX melanoma xenograft. Here we show that humanized NSG-Tg(Hu-IL15) mice mediate efficient ADCC against Daudi B lymphoma cells in vivo. Administration of anti-human CD20 antibody (rituximab) resulted in significant tumor growth inhibition, in both tumor volume and tumor weight. We observed consistent ADCC efficacy in humanized NSG-Tg (Hu-IL15) mice engrafted with three different HSC donors. Together these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells and that this mouse model enables NK cell-targeted cancer immunotherapy for preclinical testing.
Citation Format: Li-Chin Yao, Mingshan Cheng, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, James G. Keck. Humanized NSG-Tg(Hu-IL15) mice support preclinical immune-oncology efficacy for testing of NK cell-based 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 B72.
Abstract B78: NIR light-triggered photoimmunotherapy selectively destroy tumor cells in a clinically relevant desmoplastic heterocellular model
Authors: Bano Shazia 
Published: March 2020

Abstract
Near-infrared light-triggered photoimmunotherapy, utilizing the simultaneous presence of light and targeted conjugates, has emerged as a promising approach to impart selective cytotoxicity, especially for more complex nanoconstructs. Targeted immunoconjugates promise unique capabilities of combining multiple therapeutic agents within a single nanoplatform and promise great advances in revolutionizing cancer treatments, promoting selective drug localization and photo-triggered release of secondary agents to tumors cells that overexpress specific receptors. This study has utilized smart, liposome-based photoactivatable multiagent nanoconjugates, doped with a photoactivatable chromophore benzoporphyrin derivative (BPD) labeled with an active targeting ligand cetuximab to target the EGFR receptor (overexpressed on various cancer cells) for quantitative molecular imaging to measure the true in vivo receptor specificity and localized photodynamic therapy following NIR activation, that further can trigger the release of encapsulated payload to pancreatic cancer spheroids. In an in vivo model, these targeted nanoconstructs demonstrate substantial pancreatic tumor necrosis in a receptor-specific manner and modulate the collagen content in desmoplastic model of pancreatic ductal adenocarcinoma (MIA PaCa-2) in the presence of patient-derived pancreatic cancer-associated fibroblasts (PCAFs). This study establishes a tunable path towards optimally effective multiagent nanoconjugates for tumor-specific accumulation and targeted destruction of cancer cells in complex cancer model to enhance the therapeutic index of the administrated drugs.
Citation Format: Shazia Bano. NIR light-triggered photoimmunotherapy selectively destroy tumor cells in a clinically relevant desmoplastic heterocellular 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 B78.
Abstract B87: NK cells lose their ability to control MHC-I-deficient tumor cells outside circulation
Authors: Requesens Marta , Bunting Mark , Vyas Maulik , Demehri Shawn 
Published: March 2020

Abstract
A common tumor immune-evasion mechanism is downregulation of major histocompatibility complex Class-I (MHC-I) that enables malignant cell escape from cytotoxic T-cell responses. This strategy also contributes to nonresponsiveness of tumors to T-cell targeted immune-checkpoint blockade. MHC-I is an antigen-presenting molecule that also functions as an inhibitory ligand for natural killer (NK) cells. Thus, loss of MHC-I should render cells susceptible to NK cell-mediated cytotoxicity. However, this does not always occur. Previously it was demonstrated that NK cells were able to strongly reject MHC-I-deficient bone marrow cells in the circulation, yet they failed to reject MHC-I-deficient organ grafts, suggesting restricted NK cell cytotoxicity in tissues. We hypothesized that a similar NK cell tolerance to MHC-I-deficient cells occurs in the context of solid cancers. We compared NK cell recruitment and activation using WT and MHC-I-deficient B16F10 melanoma models. We demonstrated that NK cells eradicate circulating MHC-I−/− B16F10 cells, effectively preventing tumor metastasis to the lungs. In contrast, NK cells failed to clear MHC-I−/− B16F10 tumors when implanted subcutaneously, nor was the growth of these tumors affected by NK cell depletion. Interestingly, spontaneous lymph node (LN) metastasis from MHC-I-deficient solid tumors was fully abrogated in an NK cell-dependent manner, indicating functional inhibition of NK cells in peripheral tissues, but not in circulation or draining lymphatics. In conclusion, we demonstrate NK cell tolerance to MHC-I-deficient tumor cells in tissues, but not in circulation, which suggests the presence of non-MHC-I NK cell-inhibitory signals in solid organs. Our research uncovers a fundamental aspect of NK cell biology and will open up the possibility of new NK cell-based therapeutic strategies to control solid tumors that escape cytotoxic CD8+ T-cell responses by downregulating MHC-I.
Citation Format: Marta Requesens, Mark Bunting, Maulik Vyas, Shawn Demehri. NK cells lose their ability to control MHC-I-deficient tumor cells outside circulation [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 B87.
Abstract B89: Dual PD-1 and VEGFR-2 blockade induces vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma
Authors: Datta Meenal , Shigeta Kohei , Hato Tai , Kitihara Shuji , Chen Ivy X. , Matsui Aya , Kikuchi Hiroto , Mamessier Emilie , Aoki Shuichi , Ramjiawan Rakesh R. , Ochiai Hiroki , Bardeesy Nabeel , Huang Peigen , Jain Rakesh K. , Cobbold Mark , Zhu Andrew X. , Duda Dan G. 
Published: March 2020

Abstract
Introduction: Only a fraction of hepatocellular carcinoma (HCC) patients benefit from programmed death receptor-1 (PD-1) blockade. Combining PD-1 blockade with antiangiogenic treatments has been able to substantially increase the fraction of responsive HCC patients, but the mechanism of this interaction is unknown. We recapitulated these clinical outcomes (response vs. resistance) using orthotopic murine models of HCC. VEGFR2 blockade significantly delayed primary tumor growth but failed to prolong survival, while anti-PD-1 monotherapy conferred a minor survival. However, dual anti-PD-1/VEGFR-2 therapy significantly inhibited primary tumor growth and doubled survival in multiple models. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T-cell infiltration and activation, improving the ratio of anti- vs. pro-tumor-associated macrophages, and reducing T regulatory cell (Treg) infiltration in HCC tissue. Moreover, we found that VEGFR-2 blockade increased the PD-1 expression in tumor-infiltrating CD4+ cells. Under anti-PD-1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy.
Conclusion: We show that dual anti-PD-1/VEGFR-2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase survival in both anti-PD-1 therapy resistant and responsive HCC models.
Citation Format: Meenal Datta, Kohei Shigeta, Tai Hato, Shuji Kitihara, Ivy X. Chen, Aya Matsui, Hiroto Kikuchi, Emilie Mamessier, Shuichi Aoki, Rakesh R. Ramjiawan, Hiroki Ochiai, Nabeel Bardeesy, Peigen Huang, Rakesh K. Jain, Mark Cobbold, Andrew X. Zhu, Dan G. Duda. Dual PD-1 and VEGFR-2 blockade induces vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma [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 B89.
Abstract B93: Tumor lymphangiogenesis improves responsiveness to radiotherapy in mouse melanoma
Authors: Mitrousis Nikolaos , Sasso Maria Stella , Weichselbaum Ralph R. , Hubbell Jeffrey A. , Swartz Melody A. 
Published: March 2020

Abstract
Radiotherapy (RT) constitutes a significant component of clinically used cancer therapy, with approximately 50% of all cancer patients receiving treatment over the course of their disease. RT is known to induce immunogenic cell death of tumor cells, leading to the release of tumor antigens, damage-associated molecular patterns, and other tumor-resident components such as cytokines. This phenomenon drives the initiation of antigen-specific immune responses, which have been shown to be essential for the complete response to RT. Notwithstanding its broad applicability and diverse mechanisms of action, RT does not usually lead to curative responses and combinations with other treatment modalities are needed to improve efficacy. Our laboratory and others have previously demonstrated that tumor-associated lymphatics can actively influence antitumor immune responses and potentiate immunotherapy. Here, we investigate whether lymphangiogenesis influences the antitumor efficacy and immune response elicited by RT. We employed the aggressive B16F10 melanoma model, that was either transduced to overexpress the lymphangiogenic factor VEGF-C (B16-VEGF-C) or mock-transduced (B16-ctrl). Tumor-bearing animals were treated by ablative localized RT and monitored for tumor growth and survival, while antitumor immune responses were assessed by flow cytometry and ELISA. We found that the therapeutic response to RT was stronger in B16-VEGF-C melanomas compared to B16-ctrl, as evidenced by a significant delay in tumor growth and prolonged animal survival. In agreement with this finding, B16-VEGF-C melanomas exhibited a significantly greater CD8+ T-cell infiltration and activation upon ex vivo restimulation after RT. These responses were partially inhibited by a function-blocking antibody of the main VEGF-C receptor, VEGFR3. Together, our findings demonstrate that lymhangiogenesis may be a key contributing factor underlying tumor responsiveness to RT.
Citation Format: Nikolaos Mitrousis, Maria Stella Sasso, Ralph R. Weichselbaum, Jeffrey A. Hubbell, Melody A. Swartz. Tumor lymphangiogenesis improves responsiveness to radiotherapy in mouse melanoma [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 B93.