Mechanisms of resistance to immune checkpoint inhibitors.
Mechanisms of resistance to immune checkpoint inhibitors.
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DOI：
10.1038/bjc.2017.434
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发表时间：
2018-01
影响因子：
8.8
通讯作者：
Flaherty KT
中科院分区：
文献类型：
--
作者：
Jenkins RW;Barbie DA;Flaherty KT
靶向CTLA-4和PD-1/PD-L1轴的免疫检查点抑制剂（ICI）在几种类型的癌症中显示出前所未有的临床活性，并正在迅速改变医学肿瘤学的实践。尽管细胞毒性化疗和小分子抑制剂（“靶向治疗”）主要直接作用于癌细胞，但免疫检查点抑制剂通过破坏共抑制T细胞信号传导来重振抗肿瘤免疫应答。虽然在接受常规癌症治疗和靶向治疗的患者中通常会出现耐药性，但在接受ICI治疗的大部分患者中通常会观察到提示持久免疫记忆的持久应答。然而，初始反应似乎是一个二元事件，大多数对单药ICI治疗无反应者的进展速度与疾病的自然史一致。此外，随着临床试验人群的随访时间延长，现在出现了晚期复发，这表明出现了获得性耐药。由于预测临床反应和/或抗性的稳健生物标志物仍然难以捉摸，先天性（原发性）和获得性（继发性）抗性的潜在机制主要是从临床前研究和相关临床数据推断的。对ICI反应（和耐药性）的分子和免疫机制的进一步了解不仅可以识别新的预测和/或预后生物标志物，而且最终可以指导临床ICI治疗的最佳组合/测序。在这里，我们回顾了新出现的临床和临床前数据，确定了先天性和获得性免疫检查点抑制抗性的新机制。
Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer and are rapidly transforming the practice of medical oncology. Whereas cytotoxic chemotherapy and small molecule inhibitors (‘targeted therapies’) largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunologic memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addition, late relapses are now emerging with longer follow-up of clinical trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clinical response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clinical studies and correlative clinical data. Improved understanding of molecular and immunologic mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clinical and pre-clinical data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
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影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
64.5
作者：
Hugo W;Shi H;Sun L;Piva M;Song C;Kong X;Moriceau G;Hong A;Dahlman KB;Johnson DB;Sosman JA;Ribas A;Lo RS
通讯作者：
Lo RS
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH