Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment
Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment
复制标题
DOI：
10.1172/jci128644
复制
发表时间：
2019-12-02
影响因子：
15.9
通讯作者：
Yang, Yiping
中科院分区：
文献类型：
--
作者：
Petty, Amy J.;Li, Ang;Yang, Yiping
肿瘤相关巨噬细胞（TAM）通常表现出一种类似于GM2的表型，以促进肿瘤生长。然而，是什么驱动TAM的M2极化以及TAM如何抑制肿瘤微环境（TME）内的抗肿瘤免疫力仍然在很大程度上不确定。使用几种鼠肿瘤模型，我们表明髓样细胞中的刺猬（Hh）信号传导对于TAM M2极化和肿瘤生长至关重要。我们还发现，肿瘤细胞分泌音刺猬（SHH），Hh配体，和肿瘤衍生的SHH驱动TAM M2极化。此外，Hh诱导的TAM中的功能极化通过TAM抑制CXCL9和CXCL10的产生来抑制CD8（+）T细胞向TME的募集。最后，我们证明了Kruppel样因子4（Klf4）介导Hh依赖的TAM M2极化和免疫抑制功能。总的来说，这些发现突出了肿瘤源性SHH在促进TAM M2极化（TAM介导的免疫抑制机制）中的关键作用，并可能为设计新的癌症免疫策略提供见解。
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8(+) T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Kruppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.