TGFβ Promotes Immune Evasion to Limit the Efficacy of Anti–PD-1/PD-L1

Immune checkpoint blockade with antibodies targeting PD-1 or PD-L1 achieve durable responses in a subset of patients with a variety of tumor types, including metastatic urothelial and colorectal cancer. However, the determinants of response and resistance remain largely unknown. Mariathasan, Turley, Nickles, and colleagues analyzed tumor samples from 298 patients with metastatic urothelial cancer treated with the anti–PD-L1 antibody atezolizumab. Expression of PD-L1 and a CD8⁺ T-effector cell gene signature were associated with response to atezolizumab, as was a high tumor mutation or neoantigen burden. Lack of response was associated with TGFβ signaling in fibroblasts and the exclusion of CD8⁺ T cells, which was associated with a dense fibroblast- and collagen-rich stroma. In a mouse mammary carcinoma model with a similar TGFβ-activated stroma and immune cell exclusion, treatment with an anti–PD-L1 antibody has limited effects, but the addition of an antibody targeting TGFβ induced tumor regressions in a CD8⁺ T cell–dependent manner and allowed T-cell infiltration into the center of the tumors. These findings further indicate that TGFβ-mediated stromal remodeling restricts T-cell infiltration to suppress antitumor immunity, and suggest that TGFβ inhibition may enhance the efficacy of immune checkpoint blockade. In a related study, Tauriello and colleagues investigated the effects of colorectal cancer mutations on the tumor microenvironment in a newly developed genetic mouse model. Mice bearing Apc, Kras, Tgfbr2, and Trp53 mutations in the intestinal stem cells developed metastatic colorectal cancer characterized by a TGFβ-activated stroma, T-cell exclusion, and a low mutational burden. In this model, single-agent PD-1/PD-L1 inhibition had little effect, but co-targeting TGFβ produced a robust antitumor immune response that could prevent the development of metastasis and eliminate established metastases. Collectively, these studies demonstrate that a TGFβ-activated stroma can promote T-cell exclusion to reduce the efficacy of immune checkpoint blockade and suggest that inhibiting TGFβ may sensitize tumor cells to treatment with anti–PD-1/PD-L1.

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554:544–8.

Tauriello DV, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018 Feb 14 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.