MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma
MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma
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MyD 88/IL 1 R轴调节PD-1在黑色素瘤相关巨噬细胞上的表达并维持其免疫抑制功能
DOI：
10.1158/0008-5472.can-20-3510
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发表时间：
2021-05-01
期刊：
影响因子：
11.2
通讯作者：
Kanneganti, Thirumala-Devi
中科院分区：
文献类型：
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作者：
Tartey, Sarang;Neale, Geoffrey;Kanneganti, Thirumala-Devi
巨噬细胞是组织稳态、细胞增殖和肿瘤转移的关键介质。肿瘤相关巨噬细胞（TAM）通常与实体瘤中的肿瘤促进免疫抑制功能相关。在这里，我们检查了人类癌症中Toll样受体下游衔接分子的转录景观，发现MYD 88的高表达与肿瘤进展相关。在小鼠黑色素瘤中，MyD 88而不是Trif对于肿瘤进展、血管生成和维持TAM的免疫抑制表型至关重要。此外，MyD 88在髓样细胞中的表达推动了黑色素瘤的进展。MyD 88/IL 1受体（IL 1 R）轴通过促进NF-κ Bp 65募集到Pdcd 1启动子来调节TAM上的程序性细胞死亡（PD）-1表达。此外，将MyD 88抑制剂与抗PD-1阻断剂组合的组合免疫治疗方法引起了强烈的抗肿瘤作用。因此，MyD 88/IL 1 R轴维持TAM的免疫抑制功能，并通过调节PD-1表达促进肿瘤生长。意义：这些发现表明，MyD 88调节TAM的免疫抑制活性，表明巨噬细胞介导的免疫疗法结合MYD 88抑制剂与PD-1阻断剂可以在多种癌症中产生更好的治疗效果。
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-kappa Bp65 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.