Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators.
Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators.
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将全基因组CRISPR免疫筛查与多组临床数据相结合，揭示了不同类别的肿瘤内在免疫调节因子。
DOI：
10.1136/jitc-2020-001819
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Peng W
中科院分区：
文献类型：
--
作者：
Hou J;Wang Y;Shi L;Chen Y;Xu C;Saeedi A;Pan K;Bohat R;Egan NA;McKenzie JA;Mbofung RM;Williams LJ;Yang Z;Sun M;Liang X;Rodon Ahnert J;Varadarajan N;Yee C;Chen Y;Hwu P;Peng W
尽管免疫疗法被批准用于广泛的癌症，但大多数患者对免疫疗法没有反应或在初始反应后复发。这些失败可能归因于肿瘤细胞的免疫抑制机制。然而，使用常规方法系统地评估肿瘤内在因子作为癌症患者免疫调节剂的潜力是具有挑战性的。为了以公正的方式确定癌症免疫治疗无应答者的免疫抑制机制，我们进行了全基因组CRISPR免疫筛选，并将我们的结果与多组学临床数据相结合，以评估肿瘤内在因素在调节癌症免疫治疗的两个限速步骤中的作用，即T细胞肿瘤浸润和T细胞介导的肿瘤杀伤。我们的研究揭示了两种不同类型的免疫抗性调节剂，并证明了它们作为治疗靶点的潜力，以提高免疫治疗的疗效。其中，PRMT 1和RIPK 1分别被鉴定为双重免疫抗性调节剂和细胞毒性抗性调节剂。尽管不同类型的免疫疗法之间的幅度不同，但遗传靶向PRMT 1和RIPK 1使肿瘤对T细胞杀伤和抗PD-1/OX 40治疗敏感。有趣的是，RIPK 1特异性抑制剂增强了基于T细胞和抗OX 40治疗的抗肿瘤活性，尽管对T细胞肿瘤浸润的影响有限。总的来说，这些数据为合理的免疫肿瘤学组合提供了丰富的新靶点资源。
Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.
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影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
28.2
作者：
Peng W;Chen JQ;Liu C;Malu S;Creasy C;Tetzlaff MT;Xu C;McKenzie JA;Zhang C;Liang X;Williams LJ;Deng W;Chen G;Mbofung R;Lazar AJ;Torres-Cabala CA;Cooper ZA;Chen PL;Tieu TN;Spranger S;Yu X;Bernatchez C;Forget MA;Haymaker C;Amaria R;McQuade JL;Glitza IC;Cascone T;Li HS;Kwong LN;Heffernan TP;Hu J;Bassett RL Jr;Bosenberg MW;Woodman SE;Overwijk WW;Lizée G;Roszik J;Gajewski TF;Wargo JA;Gershenwald JE;Radvanyi L;Davies MA;Hwu P
通讯作者：
Hwu P
影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
影响因子：
10.1
作者：
Liadi I;Singh H;Romain G;Rey-Villamizar N;Merouane A;Adolacion JR;Kebriaei P;Huls H;Qiu P;Roysam B;Cooper LJ;Varadarajan N
通讯作者：
Varadarajan N
影响因子：
10.9
作者：
Pollack SM;Jones RL;Farrar EA;Lai IP;Lee SM;Cao J;Pillarisetty VG;Hoch BL;Gullett A;Bleakley M;Conrad EU 3rd;Eary JF;Shibuya KC;Warren EH;Carstens JN;Heimfeld S;Riddell SR;Yee C
通讯作者：
Yee C