Arginase 2 as a metabolic immune checkpoint in anti-tumor immunity

Abstract

Arginine depletion, an essential amino acid for T cells, is a major immunosuppressive mechanism for anti-tumoral T cells. Despite extensive characterisation of extracellular arginine depletion by the arginase enzyme Arg1, the role of the more ancestral Arg2 isoform in immunity, and especially in anti-tumor immunity, remained unaddressed. Preclinical murine melanoma and colorectal carcinoma models showed that, while Arg2-overexpression in tumor cells impaired adaptive anti-tumor responses, germ-line and CD8+ T cell-specific Arg2 deletion enhanced anti-tumor immune responses, reducing tumor growth. Notably, combination of Arg2 deletion and PD-1 blockade synergistically improved single-immunotherapy effects. Concomitantly, we also engineered a new mouse strain (Arg2em1Wreith), a tool for further comprehension of Arg2 post-transcriptional regulation by the immunorelevant microRNA-155. In conjunction with incipient data on human ARG2 inhibition in T cells, this thesis proposes Arg2 as a new molecular target for the improvement of T cell-based immunotherapies, at the forefront of cancer treatments in modern medicine.