Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
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DOI：
10.1038/ncomms10582
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发表时间：
2016-01-29
影响因子：
16.6
通讯作者：
Balko JM
中科院分区：
文献类型：
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作者：
Johnson DB;Estrada MV;Salgado R;Sanchez V;Doxie DB;Opalenik SR;Vilgelm AE;Feld E;Johnson AS;Greenplate AR;Sanders ME;Lovly CM;Frederick DT;Kelley MC;Richmond A;Irish JM;Shyr Y;Sullivan RJ;Puzanov I;Sosman JA;Balko JM
抗PD-1治疗在30-40%的晚期黑色素瘤患者中产生客观临床应答。由于大多数患者没有反应，因此需要预测性生物标志物来指导治疗选择。我们假设MHC-I/II表达是肿瘤抗原呈递所必需的，并且可以预测抗PD-1治疗反应。在这项研究中，在60个黑色素瘤细胞系中，我们发现MHC-II的双峰表达模式，而MHC-I的表达是普遍存在的。一个独特的黑色素瘤亚群能够在基础或IFNγ刺激条件下表达MHC-II。使用通路分析，我们表明MHC-II（+）细胞系显示出“PD-1信号”、“同种异体移植排斥”和“T细胞受体信号”等特征。在抗PD-1治疗的黑色素瘤患者的两个独立队列中，肿瘤细胞上的MHC-II阳性与治疗反应、无进展生存期和总生存期以及CD 4+和CD 8+肿瘤浸润相关。MHC-II+肿瘤可以通过黑素瘤特异性免疫组织化学使用市售的HLA-DR抗体来鉴定，以改善抗PD-1患者的选择。 免疫疗法用于治疗黑色素瘤，然而患者的反应差异很大，突出了对可以预测治疗成功的因素的需求。在这里，作者表明，肿瘤细胞表达的MHC-II分子与对治疗的良好反应和患者的总体生存率呈正相关。
Anti-PD-1 therapy yields objective clinical responses in 30–40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of ‘PD-1 signalling', ‘allograft rejection' and ‘T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4+ and CD8+ tumour infiltrate. MHC-II+ tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection. Immunotherapy is used to treat melanoma, however patient responses vary widely highlighting the need for factors that can predict therapeutic success. Here, the authors show that MHC-II molecules expressed by tumour cells are positively correlated with a good response to therapy and overall patient survival.