Editors' ChoiceCancer Immunotherapy

New connections: TGF-β in tumors

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Science Signaling  27 Feb 2018:
Vol. 11, Issue 519, eaat4115
DOI: 10.1126/scisignal.aat4115

Targeting the cytokine TGF-β in the tumor microenvironment enhances antitumor immune responses by infiltrating T cells.

Antibodies directed against either the inhibitory receptor PD-1 on T cells or its ligand PD-L1 on tumor cells have provided impressive therapeutic benefits in patients with certain advanced cancers. However, the ability of these antibodies to reinvigorate T cells and unleash antitumor immunity is successful in only a subset of patients, emphasizing the need to better understand the underlying mechanisms of action. One important obstacle to overcome is the immunosuppressive tumor microenvironment. Two studies in Nature found that the cytokine transforming growth factor–β (TGF-β) restrains the antitumor immune response by blocking T cells from infiltrating the tumor. Tauriello et al. studied mice expressing the four main mutations associated with colorectal cancer. Metastases in these mice were characterized by reduced T cell infiltration and active TGF-β in the stroma. Blocking TGF-β signaling in the tumors made them more susceptible to the effects of anti–PD-L1 antibodies, which blocked metastasis and led to increased survival. Mariathasan et al. studied samples from patients with metastatic urothelial cancer that had been treated with anti–PD-L1 therapy. Increased TGF-β signaling in patient fibroblasts was associated with a poorer response to the therapy. Studies of a mouse model of this disease showed that combined therapy with antibodies targeting TGF-β signaling and PD–L1 increased the ability of T cells to penetrate the tumors, enhanced the antitumor immune response, and induced tumor regression. A previous study by Budhu et al. in Science Signaling found that the antitumor activity of T cells was inhibited by tumor-resident regulatory T (Treg) cells, which depended on the presence of TGF-β on the Treg cell surface. A blocking antibody against TGF-β prevented immunosuppression, boosting the antitumor response. Together, these studies suggest that combination therapies that include blockade of TGF-β signaling may be of therapeutic benefit for cancer patients.

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