Tumor Immunology Team, IBISA Immunomonitoring Platform, Cancer Research Center of Marseillle, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
Department of Surgical Oncology 2, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France.
Front Immunol. 2019 Apr 26;10:877. doi: 10.3389/fimmu.2019.00877. eCollection 2019.
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-1β 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.
子宫内膜癌是发达国家女性生殖道最常见的癌症，由于老龄化和肥胖等风险因素的增加，其发病率呈上升趋势，因此趋于成为一个公共卫生问题。然而，与乳腺癌等其他肿瘤相比，其免疫环境的特征描述较少。NK 细胞是细胞毒性先天淋巴细胞，被认为是主要的抗肿瘤效应细胞类型，其功能在肿瘤中发生明显改变，参与肿瘤进展。在这里，我们在子宫内膜癌的肿瘤微环境中对肿瘤 NK 细胞进行了表型和功能特征分析。为此，我们收集了子宫内膜肿瘤、肿瘤相邻的健康组织、匹配患者的血液和健康供体的血液，以对 NK 细胞进行比较分析。首先，我们发现 NK 细胞在肿瘤浸润中减少。然后，我们比较了肿瘤和肿瘤中 NK 细胞的表型，发现与招募的 CD103 NK 细胞相比，肿瘤驻留的 CD103 NK 细胞表达更多的共抑制分子，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。我们表明，趋化因子（CXCL12、IP-10 和 CCL27）和细胞因子谱（IL-1β 和 IL-6）在肿瘤微环境中均发生改变，可能降低 NK 细胞的功能并减少其向肿瘤部位的募集。这导致我们假设肿瘤微环境降低了驻留 NK 细胞的细胞毒性，我们通过测量细胞毒性效应产物的产生和脱颗粒来证实了这一点。总之，我们的结果表明，肿瘤微环境重塑了 NK 细胞的表型和功能，以促进肿瘤进展。
