A MyD88/IL-1R axis regulates PD-1 expression on tumor-associated macrophages and sustains their immunosuppressive function in melanoma

Abstract

Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAMs) 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. Additionally, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/interleukin-1 receptor (IL-1R) 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 anti-tumor effects. Thus, the MyD88/IL-1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression.