Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• The precise immunosuppressive functions of programmed death-ligand 2 (PD-L2) in PD-1 signal blockade therapy remain incompletely understood.
• Understanding PD-L2's role is critical for optimizing cancer immunotherapy strategies.

Purpose of the Study:

• To elucidate the detailed immunosuppressive roles of PD-L2 in the context of PD-1 signal blockade therapy.
• To evaluate the impact of PD-L2 expression on antitumor immune responses and treatment resistance in preclinical models and human cancers.

Main Methods:

• Generated mouse cell lines with varying PD-L1/PD-L2 expression statuses to assess tumor growth and lymphocyte phenotypes under PD-1 blockade.
• Analyzed The Cancer Genome Atlas (TCGA) datasets for correlations between immune gene expression and PD-L1/PD-L2 in human cancers.
• Utilized immunohistochemistry (IHC) to evaluate PD-L1/PD-L2 expression and CD8+ T-cell infiltration in tumor tissues.

Main Results:

• PD-L2 expression, alone or with PD-L1, significantly suppressed antitumor immune responses, including tumor antigen-specific CD8+ T cells, in animal models.
• Tumor resistance to anti-PD-L1 monoclonal antibody (mAb) therapy was overcome by anti-PD-1 mAb or combined anti-PD-L2 mAb treatment.
• Clinical data revealed significant correlations between PD-L2 expression in the tumor microenvironment and antitumor immune responses in renal cell carcinoma (RCC) and lung squamous cell carcinoma (LUSC).

Conclusions:

• PD-L2, similar to PD-L1, plays a significant role in immune evasion within the tumor microenvironment.
• PD-1/PD-L2 blockade should be considered a key strategy for enhancing immunotherapy efficacy in cancers expressing PD-L2, such as RCC and LUSC.