Pragati Upadhyay

Differential gene expression in WT and Tim-3 KO tumor Treg.

No evidence of pathology in the intestines (colon and cecum) of Tim-3Treg KO mice.

Relationship between the expression of Tim-3 and selected cell-surface proteins on TIL Treg.

Supplementary Table 1 from Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy

Differentially expressed genes between Tim-3 KO and WT TIL Treg

Quantitation of T cell populations recovered from MC38 TIL of WT and Tim-3Treg KO mice, with or without Treg-specific co-expression of Bcl-2.

Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T-cell immunoglobulin and mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim-3–expressing Treg are a promising target to modulate tumor-specific immune responses.

Kinetics of establishment of Treg and Tim-3 expression in MC38 tumors and draining lymph nodes (dLN); validation of Treg-specific Tim-3 knockout model.

Reduced exhaustion of total CD8 T cells in Tim-3Treg KO MC38 tumors.

No effect of delayed Tim-3Treg KO on proportions of CD8 T cells in TIL or dLN.