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

Abstract

<div>AbstractPurpose:<p>To evaluate the detailed immunosuppressive role(s) of PD-L2 given that its detailed role(s) remains unclear in PD-1 signal blockade therapy in animal models and humans.</p>Experimental Design:<p>We generated mouse cell lines harboring various status of PD-L1/PD-L2 and evaluated the tumor growth and phenotypes of tumor-infiltrated lymphocytes using several PD-1 signal blockades in animal models. In humans, the correlation between immune-related gene expression and <i>CD274</i> (encoding PD-L1) or <i>PDCD1LG2</i> (encoding PD-L2) was investigated using The Cancer Genome Atlas (TCGA) datasets. In addition, PD-L1 or PD-L2 expression in tumor cells and CD8<sup>+</sup> T-cell infiltration were assessed by IHC.</p>Results:<p>In animal models, we showed that PD-L2 expression alone or simultaneously expressed with PD-L1 in tumor cells significantly suppressed antitumor immune responses, such as tumor antigen–specific CD8<sup>+</sup> T cells, and was involved in the resistance to treatment with anti-PD-L1 mAb alone. This resistance was overcome by anti-PD-1 mAb or combined treatment with anti-PD-L2 mAb. In clinical settings, antitumor immune responses were significantly correlated with PD-L2 expression in the tumor microenvironment in renal cell carcinoma (RCC) and lung squamous cell carcinoma (LUSC).</p>Conclusions:<p>We propose that PD-L2 as well as PD-L1 play important roles in evading antitumor immunity, suggesting that PD-1/PD-L2 blockade must be considered for optimal immunotherapy in PD-L2–expressing cancers, such as RCC and LUSC.</p></div>