High Baseline Levels of PD-L1 Reduce the Heterogeneity of Immune Checkpoint Signature and Sensitize Anti-PD1 Therapy in A Tumor Size-dependent Manner

Immunotherapy has revolutionized cancer treatment, yet only a subset of patients benefit from it. Studies have demonstrated that tumor PD-L1 expression levels are significantly associated with the response to PD1/PD-L1 pathway inhibition. To explore the mechanisms underlying this relationship, we generated MCA38 colorectal cancer cells with stable PD-L1 overexpression (MCA38-PD-L1) and corresponding control cells (MCA38-pCDH). These cell lines were subcutaneously injected into C57BL/6 mice (200000 cells per mouse). Tumors were collected for RNA sequencing when they reached diameters of 4-5 mm (early stage, ES) and 7-8 mm (late stage, LS). Our findings revealed that immune checkpoint molecules increased as tumors progressed. Interestingly, high PD-L1 expression reduced the expression of various other immune checkpoint molecules in a tumor size-dependent manner. This led to a decrease in the heterogeneity of immune checkpoint signature (HIS), making the tumors more sensitive to anti-PD1 antibody therapy.