Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma
Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma
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DOI：
10.1172/jci87324
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Rosenblum, Michael D.
中科院分区：
文献类型：
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作者：
Daud, Adil I.;Loo, Kimberly;Rosenblum, Michael D.
背景。免疫检查点阻断是晚期癌症的革命性治疗方法，但许多患者对治疗没有反应。为了在不断扩大的治疗方案中对患者进行分层和合理选择组合，鉴定能够预测对特定检查点抑制剂临床反应的强大生物标志物至关重要。我们对治疗前新分离的转移性黑色素瘤样本进行了多参数流式细胞术，每组20例患者，并将随后的临床反应与肿瘤免疫表型相关联。肿瘤浸润性CD8(+) T细胞亚群内程序性细胞死亡1高/细胞毒性T淋巴细胞相关蛋白4高(PD-1（hi)CTLA-4(hi)）细胞的增加与治疗反应（RR）和无进展生存（PFS）密切相关。这些细胞的功能分析揭示了部分耗尽的T细胞表型。在抗pd -1治疗期间对转移性病变的评估表明，通过肿瘤内高度活化的CD8(+) T细胞的积累来测量，T细胞衰竭的释放，对treg没有影响。我们的数据表明，部分耗竭的肿瘤浸润性CD8(+) T细胞的相对丰度预测了抗pd -1治疗的反应。该信息可用于适当选择对PD-1途径抑制有很高临床反应可能性的患者。
BACKGROUND. Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.METHODS. We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.RESULTS. Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1(hi)CTLA-4(hi)) cells within the tumor-infiltrating CD8(+) T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8(+) T cells within tumors, with no effect on Tregs.CONCLUSIONS. Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8(+) T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.