Anti-tumorigenic Activity of Human Cysteinyl-tRNA Synthetase via Immune Stimulation

Abstract

Cancer immunotherapy drug is getting the spotlight in cancer therapy field as a new method for treating patients in cancer. Its supportive role in immune system covers disadvantages from conventional treatments (chemotherapy, surgical resection and radiotherapy) by lowering toxicity, encouraging durability, and extending applicable types and stages of tumor. Here, we used aminoacyl-tRNA synthetases (ARSs), which are commonly known for ligating amino acids to their cognate tRNAs, as a new candidate for cancer immunotherapy. Even though its role as a housekeeping enzyme has been known, evidence on non-canonical function of ARSs is mounting and its involvement in human diseases has been discovered. We proved that cysteinyl-tRNA synthetase (CRS) has an ability to suppress tumor growth by stimulating immune responses. Through the screening using syngeneic mouse model, we confirmed that CRS could suppress the tumor growth. With the binding assay using different cell types, we observed that recombinant CRS bound specifically to the macrophage and induced migration and TNF-α secretion of RAW 264.7 cells in vitro. In addition, CRS showed antitumorigenic activity by inducing TNF-α secretion and infiltration of macrophages into the tumor microenvironment in vivo. Lastly, we used various cytokines and growth factors to figure out physiological condition of CRS secretion. Interestingly, CRS was secreted from colon cancer cell line in response to TNF-α and tunicamycin (ER stress). Through this work, we concluded that secreted CRS might act as a chemokine or pro-inflammatory cytokine to stimulate immune response, thereby leading to anti-tumor response.