Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells

Int J Cancer. 2013 Jun 15;132(12):2839-48. doi: 10.1002/ijc.27974. Epub 2012 Dec 19.

Abstract

Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88(-/-) mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88(-/-) mice than in wild-type mice. Although the generation of CD11b(+) Gr-1(+) MDSCs was less in Myd88(-/-) mice than in wild-type mice, Myd88(-/-) mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88(-/-) mice failed to suppress antigen-specific proliferation of CD8(+) T cells and CD4(+) T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88(-/-) mice compared with wild-type mice after tumor challenge. Furthermore, CD4(+) T cells residing in tumor-draining lymph nodes of Myd88(-/-) mice secreted more TNF-α than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Immunosuppression
  • Mice
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism*
  • Myeloid Differentiation Factor 88 / antagonists & inhibitors
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, Neoplasm
  • Myeloid Differentiation Factor 88
  • Tumor Necrosis Factor-alpha