Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer.
Immune tolerance to tumors is often associated with accumulation of myeloid-derived suppressor cells (MDSC) and an increase in the number of T-regulatory cells (Treg). In tumor-bearing mice, MDSCs can themselves facilitate the generation of tumor-specific Tregs. In this study, we demonstrate that expression of the immune stimulatory receptor CD40 on MDSCs is required to induce T-cell tolerance and Treg accumulation. In an immune reconstitution model, adoptive transfer of Gr-1+CD115+ monocytic MDSCs derived from CD40-deficient mice failed to recapitulate the ability of wild-type MDSCs to induce tolerance and Treg development in vivo. Agonistic anti-CD40 antibodies phenocopied the effect of CD40 deficiency and also improved the therapeutic efficacy of IL-12 and 4-1BB immunotherapy in the treatment of advanced tumors. Our findings suggest that CD40 is essential not only for MDSC-mediated immune suppression but also for tumor-specific Treg expansion. Blockade of CD40-CD40L interaction between MDSC and Treg may provide a new strategy to ablate tumoral immune suppression and thereby heighten responses to immunotherapy.
Pan
Ping-Ying
PY
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. ping-ying.pan@mssm.edu
Ma
Ge
G
Weber
Kaare J
KJ
Ozao-Choy
Junko
J
Wang
George
G
Yin
Bingjiao
B
Divino
Celia M
CM
Chen
Shu-Hsia
SH
D019264:Adoptive Transfer; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II