The Cytoskeleton: No Longer an Innocent Bystander in Ovarian Cancer Immunotherapy

Despite advances in precision medicine, ovarian cancer (OC) remains one of the most fatal gynecological malignancies, with mortality rates that have remained stagnant since the 1980s (1). Despite the success of immunotherapies in treating various cancers, OC has a low response rate of 8-15% to immune checkpoint inhibitors (2). Sung-Min Hwang, PhD, a postdoctoral research fellow at Weill Cornell Medicine, is working to elucidate the underlying mechanisms of immunotherapy resistance in OC. His recent work (3), supported in part by the 2022 AACR-Bristol Myers Squibb Immuno-oncology Research Fellowship, revealed a crucial role for the cytoskeletal protein transgelin. This research lays the groundwork for a novel T cell therapeutic strategy to combat this aggressive malignancy.  

Efficient import of extracellular fatty acids is essential to sustain the metabolic requirements of CD8+ T cells. Fatty acid binding protein 5 (FABP5) facilitates the import of lipids and has implications in various diseases including metabolism disorders, neurological disease, and cancer (4). Dr. Hwang and colleagues discovered that the OC tumor microenvironment (TME) disrupts FABP5 surface localization in CD8+ T cells, severely impairing their ability to import extracellular fatty acids. Further, a series of studies, including protein interaction analyses and genetic studies in mice, showed that transgelin 2 (TAGLN2), an actin-binding cytoskeletal protein, is crucial for FABP5-mediated fatty acid uptake (3).  

Typically, T cells use glucose for mitochondrial respiration; however, glucose restriction is prevalent in the lipid-rich TME of OC. Dr. Hwang and colleagues demonstrated that T cells rely on TAGLN2-FABP5 to sustain metabolic fitness using extracellular fatty acids. Single-cell transcriptomic analyses showed a reduction in TAGLN2 expression in OC-infiltrating CD8+ T cells, indicating that specific factors within the OC TME are immunosuppressive. Recognizing endoplasmic reticulum (ER) stress-related transcription factor binding sites within the Tagln2 promoter and the role of ER stress in disrupting intratumoral immune cell metabolisms and anti-tumor functions (5), Dr. Hwang and colleagues explored the impact of ER stress on TAGLN2 and found it to be a significant factor enforcing a dysfunctional state in OC-infiltrating CD8+ T cells (3). 

Ongoing clinical trials are evaluating the efficacy of T cell-based immunotherapies in OC, such as chimeric endocrine receptor (CER) T cells targeting follicle-stimulating hormone receptor positive (FSH+) ovarian tumors (NCT05316129). In experiments independent of the clinical trial, Dr. Hwang and colleagues observed that the TME in a mouse model of OC inherently limited the protective capacity of CER T cells by inducing ER stress and downregulating TAGLN2, thereby hindering lipid uptake (3). Given that tumor-induced suppression of TAGLN2 may restrict the effectiveness of CER T cells, they evaluated the efficacy of TAGLN2-overexpressing CER T cells and found that CER-TAGLN2 T cells, upon infiltrating ovarian tumors, maintained high TAGLN2 expression, improved cell surface localization of FABP5, and markedly boosted the anti-tumor response. Therefore, preserving TAGLN2 in CER T cells may offer an improved approach to overcome poor immunotherapy response that can apply not only to OC, but potentially for other cancers that respond poorly to T-cell therapies. When asked about the implications of these findings, Dr. Hwang describes this work as “transformative, offering a new paradigm in cancer immunotherapy. By identifying the unexpected role of a cytoskeletal protein in modulating T cell metabolism and function, we have provided proof-of-concept for reinvigorating the ability of dysfunctional intratumoral T cells to combat cancer.”   

Dr. Hwang credits the AACR-Bristol Myers Squibb Immuno-oncology Research Fellowship as crucial to his research trajectory. He states that “this support enabled me to pursue high-risk, high-reward experiments leading to significant breakthroughs and provided the financial stability to focus on our research. The grant has facilitated access to great scientific networks in cancer research and collaboration opportunities, accelerating the pace and impact of our work.” Moving forward, Dr. Hwang plans to establish an independent laboratory and continue developing therapeutic strategies based on these mechanistic insights. These strategies include targeted agents to modulate cytoskeleton integrity in T cells and restore their metabolic and functional capabilities within the TME, aiming to develop more effective cancer immunotherapies for patients.  

References: 

1. Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints. Int J Mol Sci. 2019;20:952. doi: 10.3390/ijms20040952.  

2. Ghisoni E, Morotti M, Sarivalasis A, Grimm AJ, Kandalaft L, Laniti DD, et al. Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nat Rev Clin Oncol. 2024;21:801-17. doi: 10.1038/s41571-024-00937-4. 

3. Hwang SM, Awasthi D, Jeong J, Sandoval TA, Chae CS, Ramos Y, et al. Transgelin 2 guards T cell lipid metabolism and antitumour function. Nature. 2024;635:1010-18. doi: 10.1038/s41586-024-08071-y. 

4. Xu B, Chen L, Zhan Y, Marquez KNS, Zhuo L, Qi S, et al. The Biological Functions and Regulatory Mechanisms of Fatty Acid Binding Protein 5 in Various Diseases. Front Cell Dev Biol. 2022;10:857919. doi: 10.3389/fcell.2022.857919. 

5. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2021;21:71-88. doi: 10.1038/s41568-020-00312-2.