TIM3⁺FOXP3⁺ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer

T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8⁺ T cells arising in chronic diseases such as cancer. In addition to exhausted CD8⁺ T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3⁺ Tregs express TIM3. TIM3⁺ Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3⁺ Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3⁺ Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8⁺ T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8⁺ T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer.