Blockade of surface-bound TGF-ß on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.
Budhu S1,2, Schaer DA1, Li Y3, Toledo-Crow R3, Panageas K4, Yang X1,2, Zhong H1,2, Houghton AN1, Silverstein SC5, Merghoub T6,2,Wolchok JD6,2,7.
Author information
1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. merghout@mskcc.org wolchokj@mskcc.org.
Abstract
Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8+ T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor-ß (TGF-ß) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident Tregs in mice. Tregs isolated from B16 tumors alone were sufficient to suppress CD8+ T cell-mediated killing, which depended on surface-bound TGF-ß on the TregsImmunosuppression of CD8+ T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor programmed cell death protein 1 (PD-1). These findings suggest that contact between Tregs and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-ß-dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically.
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