The role of arginase-1 in the development of antitumor immune response

Depletion of essential (L-tryptophan) or semi-essential (L-arginine) amino acids has been shown to suppress antitumor immune responses. Arginase-1 (ARG-1) is a cytosolic enzyme catalyzing degradation of L-arginine to L-ornithine and urea, depleting tumor microenvironment of this compound. T cells need arginine to support their proliferation in the lymph nodes and to promote their ability to kill tumor cells. Arginine deprivation is associated with down-regulation of CD3 zeta, a major signal transducer from the T cell receptor (TCR). Thus, arginine deprivation due to increased ARG-1 activity is a very smart strategy of the tumor to avoid T cell cytotoxicity and, at the same time, one of the potential targets of anti-tumor therapy. ARG-1 is overexpressed not only by cancer-associated fibroblasts, myeloid-derived suppressory cells but also numerous cancer cells such as renal cell carcinoma, breast carcinoma, prostate cancer and colorectal cancer. In my talk I will discuss the idea of targeting ARG-1 to promote anti-tumor immunity.