Abstract A146: Systematic discovery of immune regulatory mechanisms in tumor cells

D. Pan, A. Kobayashi, Peng Jiang, Guocheng Yuan, X. Liu, John G Doench, Xintao Qiu, P. Rao, Henry W. Long, Myles A. Brown, K. Wucherpfennig, L. F. Andrade, Rong En Tay, Adrienne M. Luoma, Daphne M Tsoucas, Klothilda Lim
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Abstract

Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T-cells, the central effectors of antitumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T-cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T-cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T-cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T-cells. Citation Format: Deng Pan, Aya Kobayashi, Peng Jiang, Guo-Cheng Yuan, X. Shirley Liu, John Doench, Xintao Qiu, Prakash Rao, Henry Long, Myles A. Brown, Kai W. Wucherpfennig, Lucas Ferrari de Andrade, Rong En Tay, Adrienne M. Luoma, Daphne Tsoucas, Klothilda Lim. Systematic discovery of immune regulatory mechanisms in tumor cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A146.
A146:肿瘤细胞免疫调节机制的系统发现
许多人类癌症对免疫疗法有抗药性,原因尚不清楚。我们使用基因组规模的CRISPR/Cas9筛选来鉴定肿瘤细胞抵抗细胞毒性t细胞杀伤的机制,细胞毒性t细胞是抗肿瘤免疫的中心效应物。超过100个基因的失活使小鼠B16F10黑色素瘤细胞对t细胞的杀伤敏感,包括prm1、Arid2和Brd7,它们编码SWI/SNF染色质重塑复合物的PBAF形式的成分。PBAF功能的丧失增加了肿瘤细胞对干扰素-γ的敏感性,导致募集效应t细胞的趋化因子分泌增强。当Pbrm1失活时,治疗抵抗性肿瘤对免疫治疗有反应。在许多人类癌症中,PBRM1和ARID2的表达与t细胞细胞毒性基因的表达呈负相关,并且PBRM1缺失的小鼠黑色素瘤被细胞毒性t细胞更强烈地浸润。引文格式:潘deng, Aya Kobayashi,姜鹏,袁国成,X. Shirley Liu, John Doench,邱鑫涛,Prakash Rao, Henry Long, Myles A. Brown, Kai W. Wucherpfennig, Lucas Ferrari de Andrade, Rong En Tay, Adrienne M. Luoma, Daphne Tsoucas, Klothilda Lim。肿瘤细胞免疫调节机制的系统发现[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫,2019;7(2增刊):摘要nr A146。
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