A MyD88/IL1R Axis Regulates PD-1 Expression on Tumor-Associated Macrophages and Sustains Their Immunosuppressive Function in Melanoma

Cancer Res. 2021 May 1;81(9):2358-2372. doi: 10.1158/0008-5472.CAN-20-3510. Epub 2021 Feb 22.


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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2358/F1.large.jpg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Tolerance / genetics*
  • Male
  • Melanoma / immunology*
  • Melanoma / pathology
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Signal Transduction / genetics*
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • Tumor-Associated Macrophages / immunology*


  • MYD88 protein, human
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Interleukin-1