Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function
Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function
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DOI：
10.3389/fimmu.2019.00877
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发表时间：
2019-04-26
影响因子：
7.3
通讯作者：
Olive, Daniel
中科院分区：
文献类型：
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作者：
Degos, Clara;Heinemann, Mellie;Olive, Daniel
子宫内膜癌是发达国家女性生殖道中最常见的癌症，随着老龄化、肥胖等危险因素发病率的增加，子宫内膜癌已成为一个公共卫生问题。然而，与乳腺癌等其他肿瘤相比，其免疫环境的特征较少。NK细胞是一种细胞毒性的先天淋巴样细胞，被认为是一种主要的抗肿瘤效应细胞类型，其功能在肿瘤中发生了巨大的变化，参与了肿瘤的发展。在这里，我们描述了子宫内膜癌肿瘤微环境中肿瘤NK细胞的表型和功能。为此，我们收集了子宫内膜肿瘤、癌旁正常组织、配对患者的血液和健康献血者的血液，进行了NK细胞的对比分析。首先，我们发现肿瘤浸润液中的NK细胞非常贫乏。然后，我们比较了肿瘤中NK细胞的表型，发现肿瘤常驻CD103+NK细胞与招募的CD103(-)NK细胞相比，表现出更多的共抑制分子，如Tigit和Tim-3，并且这些分子的表达随着疾病的严重程度而增加。我们发现，趋化因子(CXCL12、IP-10和CCL27)和细胞因子(IL-1β和IL-6)在肿瘤微环境中都发生了变化，可能会降低NK细胞的功能和对肿瘤部位的募集。这导致了肿瘤微环境降低常驻NK细胞的细胞毒性的假设，我们通过测量细胞毒性效应的产生和脱颗粒来证实这一假设。综上所述，我们的结果表明，肿瘤微环境重塑了NK细胞的表型和功能，促进了肿瘤的进展。
Endometrial Cancer is the most common cancer in the female genital tract in developed countries, and with its increasing incidence due to risk factors such as aging and obesity tends to become a public health issue. However, its immune environment has been less characterized than in other tumors such as breast cancers. NK cells are cytotoxic innate lymphoid cells that are considered as a major anti-tumoral effector cell type which function is drastically altered in tumors which participates to tumor progression. Here we characterize tumor NK cells both phenotypically and functionally in the tumor microenvironment of endometrial cancer. For that, we gathered endometrial tumors, tumor adjacent healthy tissue, blood from matching patients and healthy donor blood to perform comparative analysis of NK cells. First we found that NK cells were impoverished in the tumor infiltrate. We then compared the phenotype of NK cells in the tumor and found that tumor resident CD103+ NK cells exhibited more co-inhibitory molecules such as Tigit, and TIM-3 compared to recruited CD103(-) NK cells and that the expression of these molecules increased with the severity of the disease. We showed that both chemokines (CXCL12, IP-10, and CCL27) and cytokines profiles (IL-1 beta and IL-6) were altered in the tumor microenvironment and might reduce NK cell function and recruitment to the tumor site. This led to hypothesize that the tumor microenvironment reduces resident NK cells cytotoxicity which we confirmed by measuring cytotoxic effector production and degranulation. Taken together, our results show that the tumor microenvironment reshapes NK cell phenotype and function to promote tumor progression.