ABSTRACT
PD-1 and its ligand PD-L1 are major mediators of tumor-induced immunosuppression. Chitinase 3-like-1 (Chi3l1) is induced in many cancers where it portends a poor prognosis and contributes to tumor metastasis. Here we demonstrate that Chi3l1 regulates the expression of PD-L1, PD-L2, PD-1 and LAG3 in melanoma lung metastasis. Chi3l1 stimulates macrophage PD-L1 expression and mediates optimal IFN-γ-stimulated PD-L1 expression via IL-13Rα2. We also demonstrate that RIG-like helicase innate immune activation suppresses Chi3l1, PD-L1, LAG3 and pulmonary metastasis. At least additive antitumor responses were seen in metastasis models treated simultaneously with individual antibodies against PD-1 and Chi3l1. At least additive cytotoxic T cell-induced tumor cell death was also seen in co-cultures of T and tumor cells treated with antibodies that target Chi3l1 and PD-1. Thus, Chi3l1 contributes to pulmonary metastasis by stimulating the PD1-PD-L1 axis and other checkpoint molecules. The simultaneous targeting of Chi3l1 and the PD-1-PD-L1 axis, represents a promising therapeutic strategy for pulmonary metastasis.
Competing Interest Statement
JAE is a cofounder of Elkurt Pharmaceuticals and Ocean Biomedical which develop inhibitors of 18 glycosyl hydrolases as therapeutics. JAE, CGL and SK have patents relating to antibodies against Chi3l1. The other authors have declared that no conflict of interest exists.