Research ArticleImmunology

Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment

See allHide authors and affiliations

Sci. Signal.  29 Aug 2017:
Vol. 10, Issue 494, eaak9702
DOI: 10.1126/scisignal.aak9702

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Blocking immunosuppression

The antitumor effects of CD8+ T cells can be blocked in the tumor microenvironment, including through the suppressive function of regulatory T cells (Tregs). Standard in vitro systems fail to recapitulate the conditions that immune cells are exposed to in vivo. Budhu et al. used a three-dimensional, collagen-fibrin gel system to investigate the effects of CD8+ T cells on cocultured melanoma cells excised from mouse tumors. The antitumor activity of the CD8+ T cells was inhibited by the presence of tumor-derived Tregs, which depended on cell-cell contact or close proximity, required the cytokine TGF-β on the Treg cell surface, and resulted in the increased cell surface expression of the immune checkpoint receptor PD-1 on the CD8+ T cells. A blocking antibody against TGF-β prevented immunosuppression, suggesting a therapeutic strategy to inhibit Treg activity in tumors.


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–β (TGF-β) 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-β on the Tregs. Immunosuppression 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-β–dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically.

View Full Text