Vascular Normalization Was Associated with Colorectal Tumor Regression upon Anti-PD-L1 Combinational Therapy

Anti-PD-L1 therapy exhibits durable efficacy, but only in a small fraction of cancer patients. The immunosuppressive tumor microenvironment (TME) is a crucial obstacle that impedes cancer immunotherapy. Here, we found that anti-PD-L1 therapy coupled with CD4⁺ T cell depletion induced colorectal tumor regression and vascular normalization, while monotherapy only retarded tumor growth without affecting the tumor vasculature. Moreover, simultaneous PD-L1 blockade and CD4⁺ T cell depletion eradicated intratumoral PD-L1⁺ lymphoid and myeloid cell populations, while additively elevating the proportions of CD44⁺CD69⁺CD8⁺, central memory CD44⁺CD62L⁺CD8⁺, and effector memory CD44⁺CD62L^-CD8⁺ T cells, suggesting a reduction in immunosuppressive cell populations and the activation of CD8⁺ T cells in the TME. Moreover, anti-PD-L1 therapy reduced the proportions of intratumoral PD-L1⁺ immune cells and suppressed tumor growth in a CD8⁺ T cell dependent manner. Together, these results suggest that anti-PD-L1 therapy induces tumor vascular normalization and colorectal tumor regression via CD8⁺ T cells, which is antagonized by CD4⁺ T cells. Our findings unveil the positive correlation of tumor regression and vascular normalization in colorectal tumor models upon anti-PD-L1 therapy, providing a potential new strategy to improve its efficacy.