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

Abstract

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.

Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape

“…The unique presence of Tim-3 þ Tregs in tumor tissue has also been observed in multiple preclinical models, including both transplantable and de novo tumors (21). In these models, the Tim-3 þ Treg population has been shown to predominate in tumor tissue and to be more immunosuppressive than the Tim-3 À Treg population, likely as a result of increased production of IL-10 and other key effector molecules such as perforin and granzymes.…”

“…In these models, the Tim-3 þ Treg population has been shown to predominate in tumor tissue and to be more immunosuppressive than the Tim-3 À Treg population, likely as a result of increased production of IL-10 and other key effector molecules such as perforin and granzymes. Moreover, it has been suggested that Tim-3 þ Tregs have a specific role in actively promoting the development of a dysfunctional phenotype in CD8 þ TILs (21).…”

TIGIT predominantly regulates the immune response via regulatory T cells

“…We found that both the frequency of granzyme B + cells as well as the expression level of granzyme B was increased in CD8 + TILs from Tigit -/-mice after stimulation ( Figure 4C). We further examined the effect of TIGIT deficiency on antigen-specific cytokine responses in either B16F10 melanoma or MC38 colon carcinoma Among the genes upregulated in TIGIT + Tregs in TILs, Havcr2 was of particular interest, as we had previously found that TIM-3 is uniquely enriched on Tregs that accumulate in tumor tissue and express high levels of both IL-10 and perforin (25). Examination of TIM-3 and TIGIT expression in Tregs from naive and tumor-bearing mice showed that while TIM-3 was expressed on a fraction of TIGIT + Tregs in naive mice, all of the TIGIT + Tregs in tumor tissue expressed TIM-3, and at a much higher level than that observed in naive Tregs ( Figure 3D).…”

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

“…These findings suggest that selective intratumoral inactivation and conversion of CD4 Tregs through targeting Helios may represent an effective approach to cancer immunotherapy. and TIGIT, that are associated with robust immunosuppressive activity as well as dysfunctional tumor-infiltrating lymphocytes (TILs) (3,9). However, the impact of the Treg-specific Helios TF has not been investigated.…”