PD-1/PD-L1 axis suppressed homeostatic proliferation–driven antitumor immunity during recovery from lymphopenic condition.

Background: Lymphopenic condition after radiotherapy or chemotherapy might be able to create an environment to mount an efficient antitumor immunity through the homeostatic proliferation of residual or adoptive lymphocytes. However, the antitumor immunity seems to decrease rapidly with the growth of tumor, and the mechanism remain elusive. Methods: In this study, we first examined the dynamic change of PD-1 expression on T cells and analyzed the connection between PD-1 expression and the exhaustion of CTLs when the number of T cells recovered from lymphopenic conditions. Anti-PD-1/PD-L1 therapies, including anti-PD-1 antibodies, PD-1 or PD-L1 knockout by Crispr-Cas9 system, were used in the study to evaluate the role of PD-1/PD-L1 block on the antigen recognition, differentiation, activation, killing, survival and prognosis of HP cells. Results: Our study found that in the mouse model of homeostatic proliferation, although T cells proliferated continuously in lymphopenic host, the number of IFN-γ-releasing CD8+T cells rapidly decreased in course of homeostatic proliferation, indicating the immunosuppressive state in tumor microenvironment. The expression of PD-1 on T cells, increased gradually in course of homeostatic proliferation, were significantly negatively related to the cytotoxicity of effector T cell. Blocking of PD-1/PD-L1 axis by PD-1 antibody promoted HP cells to recognize tumor associated antigen (TAAs) and resulted in the activation of DC cells. It can also enhanced the number of IFN-γ-releasing CD8 + T cells and the cytotoxicity of effector T cell in lymphopenic mice. Furthermore, PD-1 antibody induced a portion of tumor-specific CTL convert to central memory T cells (TCM). Finally, we found that Crispr/Cas9-mediated knockout of PD-1 in T cells or PD-L1 in melanoma cells significantly enhanced homeostatic proliferation–driven antitumor responses and inhibited tumor growth. Conclusion: These findings suggested PD-1/PD-L1 played an important role in the formation of immune tolerance during the period of homeostatic proliferation. Anti-PD-1/PD-L1 therapies may be used to enhance antitumor immunity during recovery from lymphopenic condition after chemotherapy or radiotherapy.