Inhibition or promotion, the potential role of arginine metabolism in immunotherapy for colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing morbidity and mortality. The current diagnosis and treatment plan rely on early detection and comprehensive treatment based on surgery. Still, most patients are in the middle and advanced stage at the time of diagnosis, and the therapeutic effect is very limited. Immunotherapy is a new cancer treatment method. The most commonly used are immune checkpoint inhibitors, specifically anti PD-1/PD-L1 interaction. However, immunotherapy has limitations, with its therapeutic effect closely related to the immune response in the tumor microenvironment. In recent years, the effect of arginine metabolism disorder on the occurrence and development of cancer and tumor immune regulation has attracted wide attention. Studies have confirmed that cancer cells cannot survive without arginine and arginine metabolites. In addition, arginine is essential for the proliferation, differentiation, and survival of tumor-infiltrating lymphocytes. High arginine levels can promote the anti-tumor immune response, thus increasing the effect of tumor immunotherapy. In this paper, the molecular mechanisms of arginine metabolism in the development and immune regulation of CRC are reviewed, with the authors hoping to provide potential evidence for the development of immunotherapy for CRC. Abbreviation CRC = Colorectal cancer, dMMR = Mismatch repair deficient, MSI-H = Microsatellite highly Instability, MSS = Microsatellite stability, TME = Tumor microenvironment, MHC = Major histocompatibility complex, pMMR = Mismatch repair proficient, NOS = Nitric Oxide synthase, NO = Nitric oxide, ASS-1 = Arginine succinate synthetase 1, ASL = Argininosuccinate lyase, ARG = arginase, CAT = Cationic amino acid transporter, AGAT = Arginine-glycine amidinotransferase, ADC = Arginine decarboxylase, ADI = Arginine deiminase, ODC = Ornithine decarboxylase, GCN2 = General control non-depressible 2, mTOR = Mammalian target of rapamycin, HIF-1 = Hypoxia-inducible factor 1, VEGF = Vascular endothelial growth factor, ICI = Immune checkpoint inhibitor, ORR = Objective response rate, DCR = Disease control rate, OS = Overall survival, PFS = Progress free survival, TIL = Tumor-infiltrating lymphocyte, TCM = Central memory T cell

Keywords

• colorectal cancer
• tumor immunotherapy
• immune checkpoint
• pd-1
• arginine metabolism