High baseline levels of PD-L1 reduce the heterogeneity of immunosuppressive signature to sensitize anti-PD1 therapy in a tumor size-dependent manner

The PD-L1 tumor proportion score (TPS) is an approved predictive biomarker for patients with non-small cell lung cancer (NSCLC) receiving antiPD1/PD-L1 therapy, but the predictive accuracy remains limited. In this study, we found that PD-L1 overexpression selectively improved the efficacy of anti-PD1 therapy in large LAP0297 lung and MCA38 colorectal tumors without altering the response of small tumors to anti-PD1 therapy. It is interesting that overexpressing PD-L1 reduced the heterogeneity of immunosuppressive gene signatures in large, but not small, tumors. Moreover, retrospective analysis of a phase III study (NCT03607539) in patients with NSCLC showed that PD-L1 TPS ≥ 50% was more reliable in predicting anti-PD1 responses in patients with large tumors than in patients with small tumors. Together, these results suggest that high baseline levels of PD-L1 expression reduce the heterogeneity of immunosuppressive gene signatures to sensitize tumors to anti-PD1/PD-L1 therapy in a tumor sizedependent manner. Our findings suggest an immediately available strategy to improve the prediction of patient response to PD1/PD-L1 blockade therapy by combining PD-L1 TPS and baseline tumor volume.