Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma
Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma
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DOI：
10.1158/1078-0432.ccr-16-2848
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发表时间：
2017-08-01
影响因子：
11.5
通讯作者：
Sautes-Fridman, Catherine
中科院分区：
文献类型：
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作者：
Giraldo, Nicolas A.;Becht, Etienne;Sautes-Fridman, Catherine
目的：PD-1检查点阻断辅助治疗局限性肾透明细胞癌(CcRCC)的疗效目前尚不清楚。在这种情况下，识别肿瘤微环境(TME)预后生物标志物可能有助于确定哪些患者可以从检查点封锁中受益，并发现新的治疗靶点。实验设计：我们对一组局限性肾细胞癌患者(n=40)的肿瘤组织[肿瘤浸润性淋巴细胞(TIL)]、邻近非恶性肾组织[肾浸润性淋巴细胞(RIL)]和外周血淋巴细胞(PBL)分离的T细胞进行了多参数流式细胞仪免疫表型分析。免疫表型数据与预后和组织病理学变量、CD8(+)PD-1(+)TIL的T细胞受体(TCR)谱分析、肿瘤mRNA表达和数字定量免疫组织化学相结合。结果：在TIL表型特征的基础上，我们确定了三种主要的免疫类型：(1)免疫调节的，以CD8(+)、PD-1(+)、TIM-3(+)、LAG-3(+)TIL和CD4(+)ICOS+细胞为特征，具有Treg表型(CD25(+)CD127(-)Foxp3(+)/Helios(+)GITR(+))，发展于炎性肿瘤，树突状细胞功能紊乱，高表达PD-L1；(Ii)免疫激活，富含寡克隆/细胞毒性CD8(+)PD1(+)TIM-3(+)TIL，占肿瘤的22%；(Iii)免疫沉默，富含表现RIL样表型的TIL，占队列患者的56%。只有免疫调节型肿瘤表现出侵袭性的组织学特征，在肾切除后一年内疾病进展的风险很高，并且CD8(+)PD-1(+)TIM-3(+)和CD4(+)ICOS+PBL的表型特征。结论：在局限性肾细胞癌中，CD8(+)PD-1(+)TIM-3(+)LAG-3(+)耗竭TIL和ICOS+Treg的浸润可以识别预后不良的患者，这些患者可以受益于TME调节剂的辅助治疗和检查点阻断。这项工作还提供了能够识别它们的PBL表型标记。(C)2017年AACR。
Purpose: The efficacy of PD-1 checkpoint blockade as adjuvant therapy in localized clear cell renal cell carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help define which patients could benefit from checkpoint blockade and uncover new therapeutic targets.Experimental Design: We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue [tumor-infiltrating lymphocytes (TIL)], adjacent non-malignant renal tissue [renal-infiltrating lymphocytes (RIL)], and peripheral blood lymphocytes (PBL), in a cohort of patients (n = 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8(+) PD-1(+) TILs, tumor mRNA expression, and digital quantitative immunohistochemistry.Results: On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8(+) PD-1(+) Tim-3(+) Lag-3(+) TILs and CD4(+) ICOS+ cells with a Treg phenotype (CD25(+) CD127(-) Foxp3(+) /Helios(+) GITR(+)), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8(+) PD1(+) Tim-3(+) TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only immune-regulated tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8(+) PD-1(+) Tim-3(+) and CD4(+) ICOS+ PBL phenotypic signature.Conclusions: In localized ccRCC, the infiltration with CD8(+) PD-1(+) Tim-3(+) Lag-3(+) exhausted TILs and ICOS+ Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification. (C) 2017 AACR.