Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma
Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma
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DOI：
10.1158/2326-6066.cir-15-0225
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发表时间：
2016-05-01
影响因子：
10.1
通讯作者：
Kakimi, Kazuhiro
中科院分区：
文献类型：
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作者：
Matsushita, Hirokazu;Sato, Yusuke;Kakimi, Kazuhiro
肿瘤通常具有多种遗传改变，其中一些启动肿瘤发生。其中，一些肿瘤特异性体细胞突变导致突变蛋白具有诱导抗肿瘤免疫应答的潜力。为了检查后者与肿瘤免疫应答和患者结局的相关性，我们使用了来自97名透明细胞肾细胞癌（ccRCC）患者的全外显子组和RNA测序数据集，以鉴定预测由每个患者的自体HLA分子呈递的新表位。我们发现非沉默或错义突变的数量与患者预后无关。然而，将HLA限制性新表位的数量与HLA或β（2）-微球蛋白（β M-2）的细胞表面表达相结合揭示了A-neohi/HLA-Ahi或ABC-neohi/β（2）Mhi表型与更好的临床结果相关。然而，来自CD 8 T细胞及其效应分子[CD 8A、穿孔素（PRF 1）和颗粒酶A（GZMA）]的免疫相关基因的高表达与预后无关。这可能是由于观察到这些基因与肿瘤微环境中与免疫抑制相关的其他基因（CTLA-4、PD-1、LAG-3、PD-L1、PDL 2、IDO 1和IL 10）的表达相关。这表明与更大的抗肿瘤效应免疫应答相关的丰富的新表位被强免疫抑制微环境抵消。因此，免疫抑制分子应被视为调节ccRCC患者免疫应答的高优先级靶标。阻断这些分子通路可以与靶向新抗原的免疫疗法组合以实现协同抗肿瘤活性。(C)2016年AACR。
Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or beta(2)-microglobulin (beta M-2) revealed that an A-neohi/HLA-Ahi or ABC-neohi/beta(2)Mhi phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PDL2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. (C) 2016 AACR.