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Published on: June 12, 2021
Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy
Hridesh Banerjee1, Onyedikachi V Onyekachi1, Hector Nieves-Rosado1
1University of Pittsburgh Pittsburgh, PA United States.
Abstract:
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 Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.
Insights
Targeting T cell Immunoglobulin and Mucin 3 (Tim-3) on regulatory T cells (Treg) enhances antitumor immunity. Inhibiting Tim-3 on tumor Treg reduces tumor burden and T-cell exhaustion without affecting immune tolerance.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Regulatory T cells (Treg) suppress antitumor immunity, posing a challenge for cancer therapies.
- Targeting Treg is a promising strategy, but maintaining general immune tolerance is difficult.
- Identifying specific markers on tumor-infiltrating Treg is crucial for developing effective cancer treatments.
Purpose of the Study:
- To investigate the role of T cell Immunoglobulin and Mucin 3 (Tim-3) in tumor-infiltrating Treg function and survival.
- To determine if targeting Tim-3 on Treg can enhance antitumor immunity without compromising peripheral immune tolerance.
- To explore Tim-3 as a therapeutic target for sensitizing tumors to immunotherapy.
Main Methods:
- Utilized genetic deletion of Tim-3 in regulatory T cells (Treg) in mouse models.
- Assessed tumor growth, T-cell exhaustion, and peripheral immune homeostasis.
- Investigated the combination of Tim-3 blockade with PD-1 checkpoint inhibitors.
- Analyzed Tim-3 expression in Treg from a human clinical trial cohort.
Main Results:
- Tim-3 expression on tumor Treg is essential for their function and survival, partly via Akt and FOXO1 signaling.
- Deleting Tim-3 in Treg delayed tumor-specific T-cell exhaustion and reduced tumor burden.
- Treg-specific Tim-3 deletion enhanced the efficacy of PD-1 checkpoint blockade in resistant tumors.
- Decreased Tim-3+ tumor Treg correlated with clinical response to PD-1/LAG-3 combination therapy.
Conclusions:
- Tim-3 is a critical regulator of tumor Treg function and survival.
- Targeting Tim-3 on Treg represents a viable strategy to enhance antitumor immunity.
- Tim-3 blockade, particularly in combination with other immunotherapies, holds promise for treating cancer.
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