癌症研究
黑色素瘤
封锁
免疫疗法
特里夫
肿瘤进展
癌症免疫疗法
血管生成
转移
生物
免疫系统
巨噬细胞
受体
医学
免疫学
癌症
Toll样受体
先天免疫系统
内科学
体外
生物化学
作者
Sarang Tartey,Geoffrey Neale,Peter Vogel,R. K. Subbarao Malireddi,Thirumala-Devi Kanneganti
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-05-01
卷期号:81 (9): 2358-2372
被引量:11
标识
DOI:10.1158/0008-5472.can-20-3510
摘要
Abstract Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are generally associated with tumor-promoting immunosuppressive functions in solid tumors. Here, we examined the transcriptional landscape of adaptor molecules downstream of Toll-like receptors in human cancers and found that higher expression of MYD88 correlated with tumor progression. In murine melanoma, MyD88, but not Trif, was essential for tumor progression, angiogenesis, and maintaining the immunosuppressive phenotype of TAMs. In addition, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/IL1 receptor (IL1R) axis regulated programmed cell death (PD)-1 expression on TAMs by promoting recruitment of NF-κBp65 to the Pdcd1 promoter. Furthermore, a combinatorial immunotherapy approach combining the MyD88 inhibitor with anti–PD-1 blockade elicited strong antitumor effects. Thus, the MyD88/IL1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression. Significance: These findings indicate that MyD88 regulates TAM-immunosuppressive activity, suggesting that macrophage-mediated immunotherapy combining MYD88 inhibitors with PD-1 blockade could result in better treatment outcomes in a wide variety of cancers.
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