Regulation of Chitinase-3-like-1 in T cell enhances anti-tumoral T cell responses to suppress lung metastasis

Abstract

Abstract Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we showed that Chi3l1 expression was increased in Th2 cells while it decreased in Th1 cells by time dependent manner. In addition, Chi3l1-deficient T cells were hyper-responsive to TcR stimulation and were prone to differentiating into Th1 cells, and retroviral transduction of Chi3l1 rescue increased IFNγ expression in Chi3l1-deficient Th1 cells. Chi3l1-deficient Th1 cells showed increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice showed reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, knockdown of Chi3l1 expression in the lung using peptide-siRNA complex efficiently inhibited lung metastasis with enhanced Th1 and CTL infiltration and functions. Collectively, this study demonstrates Chi3l1 is a novel regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.