Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
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DOI：
10.1038/nature14292
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发表时间：
2015-04-16
期刊：
影响因子：
64.8
通讯作者：
Minn, Andy J.
中科院分区：
文献类型：
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作者：
Twyman-Saint Victor, Christina;Rech, Andrew J.;Maity, Amit;Rengan, Ramesh;Pauken, Kristen E.;Stelekati, Erietta;Benci, Joseph L.;Xu, Bihui;Dada, Hannah;Odorizzi, Pamela M.;Herati, Ramin S.;Mansfield, Kathleen D.;Patsch, Dana;Amaravadi, Ravi K.;Schuchter, Lynn M.;Ishwaran, Hemant;Mick, Rosemarie;Pryma, Daniel A.;Xu, Xiaowei;Feldman, Michael D.;Gangadhar, Tara C.;Hahn, Stephen M.;Wherry, E. John;Vonderheide, Robert H.;Minn, Andy J.
免疫检查点抑制剂导致令人印象深刻的临床反应，但最佳结果将需要相互结合和其他疗法。这就提出了关于非冗余和抗性机制的基本问题。在这里，我们报告了用抗CTLA 4抗体（抗CTLA 4）和放射（RT）治疗的转移性黑色素瘤患者亚组的主要肿瘤消退，并在小鼠模型中重现了这种效果。尽管联合治疗改善了照射和未照射肿瘤的反应，但耐药性很常见。对小鼠的无偏倚分析显示，耐药性是由于黑色素瘤细胞上PD-L1的上调，并与T细胞耗竭相关。因此，黑色素瘤和其他癌症类型的最佳反应需要RT、抗CTLA 4和抗PD-L1/PD-1。抗CTLA 4主要抑制调节性T细胞（T细胞），以增加CD 8 T细胞与Treg（CD 8/Treg）的比率。RT增强了肿瘤内T细胞的T细胞受体（TCR）库的多样性。总之，抗CTLA 4促进T细胞的扩增，而RT塑造扩增的外周克隆的TCR库。添加PD-L1阻断剂逆转T细胞耗竭，以减轻CD 8/Treg比率的抑制，并进一步促进寡克隆T细胞扩增。与小鼠的结果相似，在我们的临床试验中显示高PD-L1的黑色素瘤患者对RT +抗CTLA 4没有反应，表现出持续的T细胞耗竭，并迅速进展。因此，黑色素瘤细胞上的PD-L1允许肿瘤逃避基于抗CTLA 4的治疗，并且RT、抗CTLA 4和抗PD-L1的组合通过不同的机制促进应答和免疫。
Immune checkpoint inhibitors result in impressive clinical responses but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
4.4
作者：
Chen, Xi;Ishwaran, Hemant
通讯作者：
Ishwaran, Hemant
DOI：
10.1158/1078-0432.ccr-13-2648
发表时间：
2014-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Robert L;Tsoi J;Wang X;Emerson R;Homet B;Chodon T;Mok S;Huang RR;Cochran AJ;Comin-Anduix B;Koya RC;Graeber TG;Robins H;Ribas A
通讯作者：
Ribas A