Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression
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DOI：
10.1016/j.cell.2020.02.042
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发表时间：
2020-03-19
期刊：
影响因子：
64.5
通讯作者：
Haldar, Malay
中科院分区：
文献类型：
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作者：
Devalaraja, Samir;To, Tsun Ki Jerrick;Haldar, Malay
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（TAM）而不是免疫刺激性树突状细胞（DC）仍不清楚。使用多种小鼠肉瘤模型，我们发现TME诱导肿瘤细胞产生视黄酸（RA），其通过抑制DC促进转录因子Irf4使肿瘤内单核细胞分化向TAM和远离DC极化。肿瘤细胞中RA产生的遗传抑制或TME内RA信号传导的药理学抑制增加刺激单核细胞衍生的细胞，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，人单核细胞中的RA响应性基因签名与多种人肿瘤中的免疫抑制性TME相关。RA被认为是一种抗癌药物，而我们的工作证明了其通过介导的免疫抑制的致瘤能力，并为靶向该途径进行肿瘤免疫治疗提供了概念证据。
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 stimulat 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 iediated immune suppression and provide proof of concept for targeting this pathway for tumor immunotherapy.