New Discovery Shows TAGLN2 Protein Boosts T Cell Immunity Against Tumors by Enhancing Lipid Metabolism

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMNov 1 2024

T cells, which are essential for immune responses against a wide range of pathogens and tumors, rely on fatty acids for energy. Fatty-acid-binding protein 5 (FABP5) aids T cells in importing and using fatty acids for their activities. However, the regulatory mechanisms of this process remain largely unknown.

In a recent study published in Nature, a team of scientists identified a protein called transgelin 2 (TAGLN2) that plays a vital role in optimizing the uptake of fatty acids and energy production in cytotoxic or CD⁸⁺ T cells, especially under stress conditions in a tumor microenvironment.

​​​​​​​Study: Transgelin 2 guards T cell lipid metabolism and antitumour function. Image Credit: Nemes Laszlo/Shuttterstock.com

Background

The effectiveness of immune responses by T cells relies on controlled metabolic pathways and the nutrients available to the cells.

Cytotoxic CD⁸⁺ T cells are essential for immune memory and fighting tumors and infections, and they derive their energy from fatty acids. The protein FABP5 helps bring fatty acids into the T cells and directs them to the mitochondria, where fatty acid β-oxidation generates power for the T cells.

Metastatic ovarian cancer is a highly treatment-resistant form of cancer that poses unique challenges for T cells, as it is known to suppress T cells by altering their stress and energy pathways.

These changes make conventional immunotherapies ineffective against this form of ovarian cancer. Understanding how ovarian cancer disrupts the energy-processing mechanisms in T cells could help develop more effective therapies.

About the Study

The present study investigated how lipid intake is impaired in CD⁸⁺ T cells within the ovarian cancer tumor microenvironment. They used fluorescent fatty acid markers and flow cytometry to measure the intake of lipids into CD⁸⁺ T cells isolated from high-grade, serous ovarian cancer (HGSOC) patients.

They also tested healthy CD8+ T cells treated with the ascites or fluid buildup supernatant from HGSOC patients to observe whether the CD⁸⁺ T cells showed reduced lipid intake. The study also analyzed the involvement of the protein FABP5 in the lipid intake of CD⁸⁺ T cells throughout the progression of ovarian cancer in murine models.

Based on the observations of an initial increase in FABP5 expression in tumor-infiltrating CD⁸⁺ T cells and a subsequent decline, the scientists aimed to clarify the mechanisms behind the surface expression of FABP5 by investigating the actin-binding protein TAGLN2.

This protein is known to play a role in FABP5 trafficking, and therefore, they used mass spectrometry and immunoprecipitation assays to detect direct interactions between FABP5 and TAGLN2.

Furthermore, the researchers also deleted TAGLN2 in the CD⁸⁺ T cells of mouse models and observed its impact on FABP5 and lipid intake in these cells. Additionally, they examined the suppression of TAGLN2 in ovarian cancer-infiltrating T cells, hypothesizing potential tumor-driven inhibition.

The study also examined the impact of endoplasmic reticulum stress pathways on TAGLN2 levels, especially the effect of X-box binding protein 1s (XBP1s), an endoplasmic reticulum stress-induced transcription factor on TAGLN2.

Murine model CD⁸⁺ T cells were used to investigate whether suppression of either XBP1s or endoplasmic reticulum stress restored the levels of TAGLN2 and improved lipid intake in CD⁸⁺ T cells.

Major Findings

The study found that the tumor microenvironment in ovarian cancer inhibits the uptake of fatty acids or lipids by CD⁸⁺ T cells by modifying the localization and function of the fatty acid transporter protein FABP5.

The cancer-infiltrating CD⁸⁺ T cells showed a significant decrease in the extracellular fatty acid uptake in comparison to the CD⁸⁺ T cells in individuals without cancer.

The reduction in lipid uptake was linked to a 50% decline in the presence of FABP5 on the cell surface due to the influence of the tumor microenvironment, although the levels of FABP5 inside the cells remained unchanged.

Furthermore, increasing the expression of FABP5 alone did not restore the lipid intake, indicating that the ovarian cancer tumor microenvironment affected the positioning of FABP5 on the cell surface rather than its production.

The results also revealed that the protein TAGLN2 was essential for localizing FABP5 on the cell surface, which enabled the intake of fatty acids into the cells. The murine model studies showed that TAGLN2 stabilized FABP5 on the CD⁸⁺ T cell surface.

Moreover, CD⁸⁺ T cells that were deficient in TAGLN2 showed diminished expression of functional markers and reduced fatty acid intake, highlighting the importance of TAGLN2 in T cell performance.

Patients with HGSOC showed significant suppression of TAGLN2 in CD⁸⁺ T cells within ascites and the tumor microenvironment.

The study identified that the inositol-requiring enzyme one alpha (IRE1α)-XBP1s signaling pathway, which manages endoplasmic reticulum stress, also inhibits the expression of TAGLN2. Blocking the path helped maintain TAGLN2 levels and improve lipid intake in CD⁸⁺ T cells.

Conclusions

To summarize, the study found that the tumor microenvironment in ovarian cancer disrupts the CD⁸⁺ T cells' energy metabolism by altering the activity of FABP5 and TAGLN2, which impacts the intake of fatty acids into the T cells.

Therapeutic strategies targeting the IRE1α-XBP1s signaling pathway within the tumor microenvironment could restore immune function in ovarian cancer and improve the efficacy of T cell-based immunotherapy.