Expression data from cultured human monocytes. Expression data from cultured human monocytes

Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy. Overall design: To identify retinoic acid-induced gene expression changes in monocytes, we performed microarray-based gene expression profiling of human monocytes cultured under conditions that promote dendritic cell differentiation in the presence or absence of all-trans retinoic acid.

视黄酸信号通路调控单核细胞向树突状细胞或巨噬细胞分化。本研究利用基因芯片（microarrays）技术，揭示人类单核细胞暴露于视黄酸后相关的基因表达变化。免疫抑制性肿瘤微环境（tumor microenvironment, TME）是免疫治疗的主要障碍。在实体瘤中，单核细胞为何优先分化为免疫抑制性肿瘤相关巨噬细胞（tumor associated macrophages, TAMs）而非免疫刺激性树突状细胞（dendritic cells, DCs），这一问题迄今仍未阐明。我们借助多种小鼠肉瘤模型开展研究，发现肿瘤微环境可诱导肿瘤细胞产生视黄酸（retinoic acid, RA），该物质通过抑制促树突状细胞转录因子Irf4的表达，使瘤内单核细胞的分化方向偏向肿瘤相关巨噬细胞，而非树突状细胞。通过基因手段抑制肿瘤细胞的视黄酸产生，或在肿瘤微环境中通过药物阻断视黄酸信号通路，均可增加刺激性单核细胞来源细胞的数量，增强T细胞介导的抗肿瘤免疫，并与免疫检查点阻断疗法展现出显著的协同效应。进一步研究显示，人类单核细胞中的视黄酸响应基因特征，与多种人类肿瘤中的免疫抑制性肿瘤微环境呈显著相关。长期以来，视黄酸被认为是一种抗癌制剂，但本研究证实其可通过髓系细胞介导的免疫抑制发挥促肿瘤作用，并为靶向该通路开展肿瘤免疫治疗提供了概念验证。实验整体设计：为鉴定单核细胞中视黄酸诱导的基因表达变化，我们对在存在或不存在全反式视黄酸（all-trans retinoic acid）的条件下、经树突状细胞分化培养的人类单核细胞进行了基于基因芯片的基因表达谱分析。