Engagement of T Cell–Expressed PD-L1 Weakens Antitumor Immunity

Tumor cells upregulate PD-L1, which is known to enable immune escape, but the effects of T-cell expression of PD-L1 in cancer have not been conclusively established. Diskin and colleagues found that T cells are a major source of PD-L1 in pancreatic ductal adenocarcinoma (PDAC) and that T-cell expression of PD-L1 in this context is regulated by JAK–STAT signaling, antigen presentation, and soluble inflammatory mediators. This PD-L1 expression had no effect on T-cell phenotype; however, it it suppressed activation, and conditional deletion of Cd274 (encoding PD-L1) in T cells promoted tumor adaptive immunity and activation of T cells and macrophages in the tumor microenvironment (TME). Ligation of T-cell expressed PD-L1 to PD-1 caused suppressive signaling in CD4⁺ T cells, preventing their activation, promoting T_h17 differentiation, and reducing T_h1 and T_h2 polarization. This suppressive signaling occurred via a STAT3-dependent mechanism distinct from that induced by the canonical PD-L1–PD-1 interaction. Additionally, T cell–expressed PD-L1 signaling caused an anergic Tbet⁻IFNγ⁻ phenotype in CD8⁺ T cells and was as suppressive as PD-1 signaling. Notably, PD-L1–expressing T cells suppressed the function of neighboring effector T cells in the PDAC TME via the canonical PD-L1–PD-1 pathway and promoted tumorigenesis. Also, PD-L1–expressing T cells polarized nearby macrophages to induce a tolerogenic, M2-like phenotype in a STAT6-dependent manner, severely weakening antitumor adaptive immunity. This work thus shows that PD-L1 expression by T cells has a tolerogenic effect on tumor immunity via multiple distinct mechanisms, demonstrating that there is a role for T cell–expressed PD-L1 in cancer, which may be important to investigate further in studies of anti–PD-L1 and anti–PD-1 therapies.

Diskin B, Adam S, Cassini MF, Sanchez G, Liria M, Aykut B, et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol 2020 Mar 9 [Epub ahead of print].

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