PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity

TLDR

PD‑L1’s role in tumor immune evasion is uncertain, as it may simply reflect an inflamed tumor microenvironment rather than actively suppressing immunity. The authors evaluated PD‑L1 on tumor versus non‑tumor cells using three mouse tumor models responsive to PD‑1 blockade. In B16 and engineered melanoma, PD‑L1 on non‑tumor cells is essential for immune suppression, whereas in the highly immunogenic MC38 colorectal adenocarcinoma, PD‑L1 expressed by tumor cells alone suffices to inhibit CD8⁺ T‑cell cytotoxicity, confer a growth advantage, and demonstrate that both tumor‑ and host‑derived PD‑L1 contribute to immunosuppression, with reduced cytotoxicity being the key mechanism.

Abstract

It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.