TIGIT Blockade Potentiates the Anti-Leukemic Activity of Exercise-Mobilized Donor Lymphocytes and Expanded γδ T-Cells

Area of Science:

• Immunology
• Cancer Therapy
• Exercise Science

Background:

• Donor lymphocyte infusion (DLI) and gamma delta (γδ) T-cells are used in leukemia treatment post-transplant but face limitations like immune exhaustion and graft-versus-host disease.
• The leukemic tumor microenvironment (TME) can inhibit the function of adoptive cell therapies (ACTs).
• Acute exercise is an emerging strategy to enhance cellular immunotherapies by mobilizing cytotoxic lymphocytes.

Purpose of the Study:

• To investigate how exercise-mobilized lymphocytes and exercise-expanded γδ T-cells interact with TIGIT checkpoint blockade to enhance anti-leukemic activity.
• To evaluate the combined therapeutic potential of TIGIT blockade with exercise-enhanced γδ T-cell therapy in a leukemia mouse model.

Main Methods:

• Healthy participants underwent acute exercise, and their peripheral blood mononuclear cells (PBMCs) and ex vivo expanded γδ T-cells were analyzed for phenotype and cytotoxicity against leukemia cells with TIGIT inhibition.
• The efficacy of combining TIGIT blockade with rest- or exercise-expanded γδ T-cells was assessed in NSG-IL15 mice bearing K562-luc leukemia.

Main Results:

• Acute exercise increased circulating CD8+ and γδ T-cells expressing TIGIT and PD-1.
• Exercise-expanded γδ T-cells showed increased PD-1, TIGIT, and DNAM-1 co-expression, with enhanced cytotoxicity amplified by TIGIT blockade.
• In vivo, TIGIT-treated, exercise-expanded γδ T-cells improved tumor suppression and prolonged tumor-free survival in mice.

Conclusions:

• Exercise primes DLI and γδ T-cell products for improved responsiveness to TIGIT checkpoint inhibition.
• Targeting TIGIT enhances DNAM-1 dependent cytotoxicity, improving anti-leukemic activity.
• Combining exercise-enhanced DLI and γδ T-cell therapies with immune checkpoint blockade offers a safe strategy to improve leukemia relapse control.