Researchers found that ovarian tumors hinder T cells’ vitality provide by trapping a key protein, blocking lipid uptake. A brand new strategy to reprogram T cells might improve immunotherapy for aggressive cancers.
Researchers at Weill Cornell Medicine have uncovered a mechanism by which ovarian tumors weaken immune cells, successfully blocking their vitality supply and hindering their capacity to launch an assault. Published on October 23 in Nature, this discovery presents a possible new immunotherapy technique for ovarian most cancers, a notoriously aggressive and difficult illness to deal with.
A big impediment in treating ovarian most cancers is the tumor microenvironment—the advanced ecosystem of cells, molecules and blood vessels that shields most cancers cells from the immune system. Within this hostile atmosphere, T cells lose their capacity to take up the lipid (fats) molecules, that are needed for vitality to mount an efficient assault.
“T cells rely on lipids as fuel, burning them in their mitochondria to power their fight against pathogens and tumors,” defined senior writer, Dr. Juan Cubillos-Ruiz, The William J. Ledger, M.D., Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. “However, the molecular mechanisms that govern this critical energy supply are still not well understood.”
Identifying How Tumors Block T-Cell Energy Supply
Lipids are considerable in ovarian tumors, however T cells appear unable to make the most of them on this atmosphere. “Researchers have focused on a protein called fatty acid-binding protein 5, or FABP5, which facilitates lipid uptake, but its exact location within the T cell remained unclear,” stated Dr. Sung-Min Hwang, a postdoctoral affiliate in Dr. Cubillos-Ruiz’s lab who led the brand new examine. Dr. Hwang found that in patient-derived tumor specimens and mouse fashions of ovarian most cancers, FABP5 turns into trapped contained in the cytoplasm of T cells as a substitute of shifting to the cell floor, the place it might usually assist take up lipids from the environment.
“That was the ‘aha!’ moment; since FABP5 is not getting to the surface, it couldn’t bring in the lipids necessary for energy production. But we still needed to figure out why,” stated Dr. Cubillos-Ruiz, who can also be co-leader of the Cancer Biology Program within the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Working with collaborators, the researchers used a battery of biochemical assays to establish proteins that bind to FABP5. They discovered a protein referred to as Transgelin 2 that interacts with FABP5 and helps transfer it to the cell floor.
Further experiments revealed that ovarian tumors suppress the manufacturing of Transgelin 2 in infiltrating T cells. Delving deeper, the researchers found that the transcription issue XBP1, which is activated by the hectic circumstances inside the tumor, represses the gene encoding Transgelin 2. Without Transgelin 2, FABP5 is trapped within the cytoplasm of T cells, stopping lipid uptake and rendering the T cells unable to assault the tumor.
Designer Immunotherapies to Overcome Tumor Defenses
With this elementary mechanism labored out, the workforce explored an immunotherapy referred to as chimeric antigen receptor T (CAR T) cells. This strategy collects a affected person’s T cells, engineers them to assault tumor cells after which injects the designer cells into the affected person. “CAR T cells work well against hematological cancers like leukemia and lymphoma, but they’re really not effective for solid tumors like ovarian or pancreatic cancers,” Dr. Cubillos-Ruiz stated.
When Dr. Hwang and his colleagues examined CAR T cells, that are presently being evaluated in medical trials, in mouse fashions of metastatic ovarian most cancers, they discovered the identical downside—Transgelin 2 repression and impaired lipid uptake. Just like regular T cells within the tumor microenvironment, the engineered CAR T cells had FABP5 tangled within the cytoplasm. As a consequence, the CAR T cells had been unable to entry lipids for vitality to successfully assault the tumor, highlighting a crucial barrier in utilizing this immunotherapy for strong tumors like ovarian most cancers.
To resolve the issue, the researchers inserted a modified Transgelin 2 gene that couldn’t be blocked by stress transcription components, so expression of the crucial protein was preserved. This allowed Transgelin 2 to chaperone FABP5 to the floor of the CAR T cells the place it might take up lipids.
Indeed, the upgraded T cells had been rather more efficient in attacking ovarian tumors than the unique CAR T cells. “Our findings reveal a key mechanism of immune suppression in ovarian cancer and suggest new avenues to improve the efficacy of adoptive T cell immunotherapies in aggressive solid malignancies,” Dr. Cubillos-Ruiz stated.
Reference: “Transgelin 2 guards T cell lipid metabolism and antitumour function” by Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A. Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T. McBain, Bikash Mishra, Lionel B. Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana Okay. Morales, Xiaoqing Yu, Paulo C. Rodriguez, Jose R. Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song and Juan R. Cubillos-Ruiz, 23 October 2024, Nature.
DOI: 10.1038/s41586-024-08071-y
This work was supported partly by the National Institutes of Health grants R01 NS114653, CA271619, CA282072, R01 CA237154 and R01 CA269382, the U.S. Department of Defense grants W81XWH2010191, W81XWH-16-1-0438, W81XWH-22-OCRP-IIRA, W81XWH2110478 and W81XWH2110357, and the American Association for Cancer Research; AACR-Bristol Myers Squibb Immuno-Oncology Research Fellowship.
