Transgelin 2 guards T cell lipid metabolism and antitumour function

Area of Science:

• Immunology
• Cellular Metabolism
• Cancer Biology

Background:

• Effective immunity against tumors requires T cell metabolic reprogramming by fatty acids.
• Fatty-acid-binding protein 5 (FABP5) is vital for lipid import and mitochondrial respiration in CD8+ T cells.
• Mechanisms governing the T cell immunometabolic axis are not fully understood.

Purpose of the Study:

• To investigate the role of cytoskeletal organizer transgelin-2 (TAGLN2) in T cell metabolism and anti-cancer function.
• To elucidate the interaction between TAGLN2, FABP5, and T cell bioenergetics.
• To explore TAGLN2's potential in overcoming tumor-induced T cell dysfunction for improved immunotherapy.

Main Methods:

• Investigated TAGLN2's role in fatty acid uptake, mitochondrial respiration, and CD8+ T cell anti-cancer activity.
• Examined TAGLN2-FABP5 interactions in activated CD8+ T cells.
• Analyzed TAGLN2 expression in ovarian cancer specimens and its correlation with ER stress.
• Assessed the impact of restoring TAGLN2 in ER-stressed T cells and in chimeric antigen receptor T cells in mouse models.

Main Results:

• TAGLN2 is essential for optimal fatty acid uptake, mitochondrial respiration, and anti-cancer function in CD8+ T cells.
• TAGLN2 interacts with FABP5, facilitating its cell surface localization and function.
• Tumor-induced endoplasmic reticulum (ER) stress downregulates TAGLN2 in infiltrating CD8+ T cells, leading to dysfunction.
• Restoring TAGLN2 enhances lipid uptake, mitochondrial respiration, and cytotoxic capacity of ER-stressed T cells.
• TAGLN2-overexpressing CAR T cells demonstrated therapeutic efficacy in metastatic ovarian cancer models, bypassing ER stress.

Conclusions:

• Cytoskeletal TAGLN2 plays a critical role in T cell lipid metabolism and anti-tumor immunity.
• The TAGLN2-FABP5 axis is a key regulator of T cell metabolic fitness and function.
• Targeting TAGLN2 presents a promising strategy to enhance cellular immunotherapy for solid tumors by preserving T cell function under stress.