Expression of Tim-3 drives Treg to an effector-like state with enhanced suppressive activity and altered response to tumor

Abstract

Abstract Regulatory T cells (T reg) are mediators effective anti-tumor immunity. We and others previously reported that 40–60% percent of T reg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs. Tumor-infiltrating Tim-3+ T reg also have enhanced suppressive function. Using a novel mouse model with cell type-specific inducible Tim-3 expression, we show here that expression of Tim-3 by T reg is sufficient to drive Treg to a more effector-like phenotype, resulting in enhanced suppressive activity and increased tumor growth. TIM-3 +T reg also seem to be metabolically altered driven by active signaling in ERK and m-TOR pathway. We further see that T reg specific deletion of TIM-3 leads to decrease in T reg frequency in tumor infiltrating lymphocytes and delay in tumor progression. These findings suggest to a possibility of using Tim-3 as a target to alter the tumor progression and clearance highliting a qualitatively different role for TIM-3 in T reg cells. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of T reg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of T reg and alter immune response in this manner.