MyD88/IL-1R axis sustains immunosuppressive function of TAMs by regulating PD-1 expression in melanoma

Macrophages are critical mediators of tissue homeostasis, cell proliferation, angiogenesis and tumor metastasis. The presence of TAMs is generally associated with tumor-promoting immunosuppressive function in solid tumors. These macrophages are widely acknowledged as one of the central suppressive populations within tumors, blocking effective T-cell responses. In the present study, we examined the transcriptional landscape of adaptor molecules downstream of TLRs in human cancers and found that higher expression of MYD88 is very well correlated with the tumor progression. In addition, we also found that mouse MyD88 but not TRIF, is essential for tumor progression and angiogenesis in melanoma. Interestingly, MyD88 is critical to maintain the immunosuppressive phenotype of TAMs in the tumors. Moreover, we found that interleukin-1 receptor (IL-1R)-Myd88 axis regulates programmed cell death (PD)-1 expression on TAMs by promoting the recruitment of phospho-NF-κB p65 to the CR-C region of the Pdcd1 promoter. Using myeloid-cell specific MyD88 mutant mice, we also showed that MyD88 expression in myeloid cells alone is sufficient to drive the melanoma progression. Thus, IL-1R/MyD88 axis maintains the immunosuppressive function of tumor-tissue macrophages to promote tumor growth by regulating PD-1/PD-L1 expression We used microarrays to compare the global transcription profiles of tumor-associated macrophages (TAMs) from WT and MyD88-null mice after engraftment of B16-F10 melanoma cells