Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell. 2020 Mar 19;180(6):1098-1114.e16. doi: 10.1016/j.cell.2020.02.042. Epub 2020 Mar 12.
The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
免疫抑制性肿瘤微环境（TME）是免疫治疗的主要障碍。在实体瘤中，为什么单核细胞优先分化为免疫抑制性肿瘤相关巨噬细胞（TAMs）而不是免疫刺激树突状细胞（DCs）仍不清楚。使用多种鼠肉瘤模型，我们发现 TME 诱导肿瘤细胞产生视黄酸（RA），通过抑制促进 DC 的转录因子 Irf4，使肿瘤内单核细胞分化向 TAMs 而不是 DC 方向极化。在肿瘤细胞中遗传抑制 RA 的产生或在 TME 中抑制 RA 信号转导会增加刺激单核细胞衍生细胞，增强 T 细胞依赖性抗肿瘤免疫，并与免疫检查点阻断协同作用。此外，人类单核细胞中 RA 反应性基因特征与多种人类肿瘤中免疫抑制性 TME 相关。RA 一直被认为是一种抗癌药物，而我们的工作通过髓样细胞介导的免疫抑制证明了它的致瘤能力，并为靶向该途径进行肿瘤免疫治疗提供了概念验证。
