Programmed death-ligand 1 expression on CD22-specific chimeric antigen receptor-modified T cells weakens antitumor potential.

Abstract

The molecules of programmed cell death protein‐1 (PD‐1) and ligand‐1 (PD‐L1) become new therapeutic targets for cancer therapy. Although tumor‐expressed PD‐L1 molecule is frequently dispensable for checkpoint blockade in some cancer patients, recent studies suggest that T cell‐expressed PD‐L1 molecule might play a crucial role in antitumor immunity. Here, to investigate CD22 chimeric antigen receptor (CAR)‐T cell therapy, we have generated the different CD22 CAR‐T constructs. We noticed that tumor cells induced PD‐L1 expression on the surface of CD22 CAR‐T cells. The induced PD‐L1 might limit immunogenic responses of CAR‐T cells. T cell‐expressed PD‐L1 leads to a suppressive signal by PD‐1/PD‐L1 engagement of CD22 CAR‐T cells. Meanwhile, PD‐L1 suppresses CD22 CAR‐T cell differentiation into memory T cells and negatively affected secretions of several essential cytokines, such as interleukin‐2 (IL‐2) and tumor necrosis factor (TNF)‐α. We further observed that anti‐PD‐L1 monoclonal antibodies rescued cytokine secretion of CD22 CAR‐T cells rather than anti‐PD‐1 monoclonal antibodies. Our current studies provide a potential mechanism to understand the functions and roles of T cell‐expressed PD‐L1 in tumor microenvironment. These results will encourage the physicians to re‐recognize the important roles of PD‐L1 in cancer immunotherapy studies and provide the helpful guidance for clinical operation of PD‐L1 inhibition drugs.