Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a genetic test to select patients for immunotherapy targeting PD-1 and/or CTLA-4 without limitation to cancer type. However, it is unclear whether the MSI-H would broadly alter the tumor microenvironment to confer the therapeutic response of different cancer types to immunotherapy. To fill in this gap, we performed an in silico analysis of tumor immunity among different MSI statuses in five cancer types. We found that consistent with clinical responses to immunotherapy, MSI-H and non-MSI-H samples from colorectal cancer (COAD-READ) exhibited distinct infiltration levels and immune phenotypes. Surprisingly, the immunological difference between MSI-H and non-MSI-H samples was diminished in stomach adenocarcinoma and esophageal carcinoma (STAD-ESCA) and completely disappeared in uterine corpus endometrial carcinoma (UCEC). Regardless of cancer types, the abundance of tumor-infiltrating immune cells, rather than MSI status, strongly associated with the clinical outcome. Since preexisting antitumor immune response in the tumor (hot cancer) is accepted as a prerequisite to the therapeutic response to anti-PD-1/CTLA-4 immunotherapy, our data demonstrate that the impact of MSI varied on immune contexture will lead to the further evaluation of predictive immunotherapy responsiveness based on the universal biomarker of MSI status.

中文翻译：

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微卫星不稳定性状态与人类癌症中的肿瘤内免疫微环境存在差异。

基于结直肠癌的临床结果，高微卫星不稳定性 (MSI-H) 最近已被美国食品和药物管理局 (FDA) 批准作为一种基因测试，用于选择针对 PD-1 和/或 CTLA-4 进行免疫治疗的患者，但不限于此到癌症类型。然而，目前尚不清楚 MSI-H 是否会广泛改变肿瘤微环境以赋予不同癌症类型对免疫疗法的治疗反应。为了填补这一空白，我们进行了计算机模拟分析五种癌症类型中不同 MSI 状态之间的肿瘤免疫。我们发现，与免疫疗法的临床反应一致，来自结直肠癌 (COAD-READ) 的 MSI-H 和非 MSI-H 样本表现出不同的浸润水平和免疫表型。令人惊讶的是，MSI-H 和非 MSI-H 样本之间的免疫学差异在胃腺癌和食管癌 (STAD-ESCA) 中减少，在子宫体子宫内膜癌 (UCEC) 中完全消失。无论癌症类型如何，肿瘤浸润免疫细胞的丰度，而不是 MSI 状态，与临床结果密切相关。由于肿瘤（热癌）中预先存在的抗肿瘤免疫反应被认为是对抗 PD-1/CTLA-4 免疫疗法的治疗反应的先决条件，