Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.
Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.
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RNA剪接的药理调节增强抗肿瘤免疫力。
DOI：
10.1016/j.cell.2021.05.038
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发表时间：
2021-07-22
期刊：
影响因子：
64.5
通讯作者：
Bradley RK
中科院分区：
文献类型：
--
作者：
Lu SX;De Neef E;Thomas JD;Sabio E;Rousseau B;Gigoux M;Knorr DA;Greenbaum B;Elhanati Y;Hogg SJ;Chow A;Ghosh A;Xie A;Zamarin D;Cui D;Erickson C;Singer M;Cho H;Wang E;Lu B;Durham BH;Shah H;Chowell D;Gabel AM;Shen Y;Liu J;Jin J;Rhodes MC;Taylor RE;Molina H;Wolchok JD;Merghoub T;Diaz LA Jr;Abdel-Wahab O;Bradley RK
虽然DNA中的突变是决定对免疫检查点阻断的反应的新抗原的最佳研究来源，但癌细胞内RNA剪接的改变可能类似地导致新表位的产生。然而，这种剪接衍生的表位的内源性抗原性和临床潜力尚未被测试。在这里，我们证明了通过特定药物类别对剪接的药理学调节产生了真正的新抗原和增强的抗肿瘤免疫力，增强了检查点免疫治疗。剪接调节以依赖于宿主T细胞和肿瘤MHC I类上呈递的肽的方式抑制肿瘤生长并增强检查点阻断。剪接调节在肿瘤类型中诱导定型剪接变化，改变MHC I结合的免疫肽组以产生剪接衍生的新表位，其在体内触发抗肿瘤T细胞应答。这些数据明确地将剪接调节鉴定为免疫原性肽的未开发来源，并提供了一种增强对检查点阻断的应答的方法，该方法易于转化为临床。通过刺激免疫细胞识别的“新抗原”的产生，调节RNA剪接的药物可以增强癌症免疫治疗。在这里，我们提出了明确的概念证据，即RNA剪接的药理学调节通过产生内源性错误剪接的抗原肽来增强抗肿瘤免疫力，并增强免疫检查点阻断的功效。
While mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes which trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic. By provoking production of “neoantigens” that are recognized by immune cells, drugs that modulate RNA splicing can enhance cancer immunotherapy. Here, we present definitive proof of concept that pharmacologic modulation of RNA splicing enhances anti-tumor immunity via the generation of endogenous, mis-spliced antigenic peptides and augments the efficacy of immune checkpoint blockade.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
影响因子：
8.8
作者：
Jayasinghe RG;Cao S;Gao Q;Wendl MC;Vo NS;Reynolds SM;Zhao Y;Climente-González H;Chai S;Wang F;Varghese R;Huang M;Liang WW;Wyczalkowski MA;Sengupta S;Li Z;Payne SH;Fenyö D;Miner JH;Walter MJ;Cancer Genome Atlas Research Network;Vincent B;Eyras E;Chen K;Shmulevich I;Chen F;Ding L
通讯作者：
Ding L
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.