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

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Programmed cell death protein-1 (PD-1) and its ligand PD-L1 are key regulators of immune responses and emerging cancer therapy targets.
• While tumor-expressed PD-L1's role is debated, T cell-expressed PD-L1 may significantly impact anti-tumor immunity.

Purpose of the Study:

• To investigate the role of T cell-expressed PD-L1 in CD22 chimeric antigen receptor (CAR)-T cell therapy.
• To understand how tumor cells influence PD-L1 expression on CAR-T cells and its functional consequences.

Main Methods:

• Generation of various CD22 CAR-T cell constructs.
• Analysis of PD-L1 expression on CD22 CAR-T cells induced by tumor cells.
• Assessment of the impact of T cell-expressed PD-L1 on CAR-T cell function, differentiation, and cytokine secretion.
• Evaluation of anti-PD-L1 and anti-PD-1 monoclonal antibodies in rescuing CAR-T cell function.

Main Results:

• Tumor cells induced PD-L1 expression on CD22 CAR-T cells, potentially limiting their anti-tumor responses.
• T cell-expressed PD-L1 engagement with PD-1 led to suppressive signals, impaired memory T cell differentiation, and reduced essential cytokine secretion (IL-2, TNF-α).
• Anti-PD-L1 antibodies effectively restored cytokine secretion, whereas anti-PD-1 antibodies did not.

Conclusions:

• T cell-expressed PD-L1 plays a critical suppressive role in the tumor microenvironment during CAR-T cell therapy.
• Targeting PD-L1 on CAR-T cells, rather than PD-1, is a promising strategy to enhance anti-tumor immunity.
• These findings offer insights into PD-L1 function and guide clinical strategies for PD-L1 inhibition in cancer immunotherapy.