Elsalys Biotech SA, Lyon, France.
Université Claude Bernard Lyon 1, INSERM U1052 CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Front Immunol. 2020 Sep 25;11:564133. doi: 10.3389/fimmu.2020.564133. eCollection 2020.
Tumor-infiltrating myeloid cells are a key component of the immune infiltrate often correlated with a poor prognosis due to their capacities to sustain an immunosuppressive environment. Among membrane receptors implicated in myeloid cell functions, Tyro3, Axl, and MerTK, which are a family of tyrosine kinase receptors (TAM-R), have been described in the regulation of innate cell functions. Here, we have identified MerTK among TAM-R as the major marker of both human M2 macrophages and tolerogenic dendritic cells (DC). , MerTK expression was found within the immune infiltrate in multiple solid tumors, highlighting its potential role in cancer immunity. TAM-R ligands Gas6 and PROS1 were found to be constitutively produced by myeloid cells . Importantly, we describe a novel function of MerTK/PROS1 axis in the regulation of IL-10 production by tolerogenic DC. Finally, the analysis of TAM-R expression within the lymphoid compartment following activation revealed that MerTK, but not Axl or Tyro3, is expressed on activated B lymphocytes and regulatory T cells, as well as CD4 and CD8 T cells. Thus, our findings deepen the implication of MerTK in the regulation of myeloid cell-mediated immunosuppression and identified new cellular targets expressing MerTK that could participate in the antitumor immune response.
肿瘤浸润髓系细胞是免疫浸润的一个关键组成部分，由于其维持免疫抑制环境的能力，常与预后不良相关。在涉及髓系细胞功能的膜受体中，酪氨酸激酶受体（TAM-R）家族中的 Tyro3、Axl 和 MerTK 已被描述在先天细胞功能的调节中。在这里，我们确定了 MerTK 是人类 M2 巨噬细胞和耐受性树突状细胞（DC）的主要标志物之一。MerTK 表达在多种实体瘤的免疫浸润中，突出了其在癌症免疫中的潜在作用。TAM-R 配体 Gas6 和 PROS1 被发现由髓系细胞组成性产生。重要的是，我们描述了 MerTK/PROS1 轴在调节耐受性 DC 产生 IL-10 中的新功能。最后，对激活后淋巴区室中 TAM-R 表达的分析表明，MerTK 而不是 Axl 或 Tyro3，表达于活化的 B 淋巴细胞和调节性 T 细胞以及 CD4 和 CD8 T 细胞上。因此，我们的研究结果加深了 MerTK 在调节髓系细胞介导的免疫抑制中的作用，并确定了表达 MerTK 的新细胞靶标，这些靶标可能参与抗肿瘤免疫反应。
