细胞毒性T细胞
免疫疗法
癌症研究
CD8型
免疫检查点
T细胞
启动(农业)
肾细胞癌
封锁
细胞毒性
癌症免疫疗法
医学
免疫系统
体内
免疫
免疫学
PD-L1
渗透(HVAC)
生物
肿瘤浸润淋巴细胞
细胞
CTLA-4号机组
肿瘤微环境
过继性细胞移植
肾透明细胞癌
激酶
作者
Jiayuan Chen,Jiazhi Mo,Jinchang Wei,Mengnan Qu,Jie Dai,Yan Kong,Huayan Xu,Juan Li,Xieqiao Yan,Chuanliang Cui,Lu Si,Zhihong Chi,Jun Guo,Xiaowen Wu,Xinan Sheng
标识
DOI:10.1002/advs.202514600
摘要
Immune checkpoint blockade (ICB) therapy, especially in combination regimens, has significantly increased survival of renal cell carcinoma (RCC) patients. However, the ICB-resistant mechanisms remain largely unclear and require further investigation. Here, an immunosuppressive ecosystem in ICB-resistant tumors is identified, featured by preferential infiltration of MARCO+ tumor-associated macrophages (TAMs) and restrained cytotoxicity of CD8+ cytotoxic T lymphocytes (CTLs). The infiltrated MARCO+ TAMs can obstruct the development of CD8+ CTLs by impairing MHC-I-mediated neoantigen cross-presentation. Mechanistically, MARCO up-regulates the expression of SOCS1, which obstructs the kinase activity of JAK1, thereby downregulating MHC-I expression through the inhibition of the JAK1-STAT1-NLRC5 signaling cascade. Further, MARCO blockade significantly facilitates ICB therapy in in vivo models by recovering tumor recognition and priming anti-tumor CD8+ T cell responses. Taken together, these findings highlight MARCO as a highly desirable target in ICB-refractory individuals for immunorecognition reignition and immunotherapy modulation.
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