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 may improve immunotherapy for aggressive cancers.
Researchers at Weill Cornell Medication have uncovered a mechanism by which ovarian tumors weaken immune cells, successfully blocking their vitality supply and hindering their capacity to launch an assault. Printed 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 complicated ecosystem of cells, molecules and blood vessels that shields most cancers cells from the immune system. Inside this hostile surroundings, T cells lose their capacity to take up the lipid (fats) molecules, that are essential for vitality to mount an efficient assault.
“T cells depend on lipids as gasoline, burning them of their mitochondria to energy their struggle in opposition to pathogens and tumors,” defined senior creator, Dr. Juan Cubillos-Ruiz, The William J. Ledger, M.D., Distinguished Affiliate Professor of An infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medication. “Nevertheless, the molecular mechanisms that govern this important vitality provide are nonetheless not nicely understood.”
Figuring out How Tumors Block T-Cell Power Provide
Lipids are ample in ovarian tumors, however T cells appear unable to make the most of them on this surroundings. “Researchers have targeted on a protein known as fatty acid-binding protein 5, or FABP5, which facilitates lipid uptake, however its precise location throughout the T cell remained unclear,” mentioned 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 will usually assist take up lipids from the environment.
“That was the ‘aha!’ second; since FABP5 shouldn’t be attending to the floor, it couldn’t convey within the lipids essential for vitality manufacturing. However we nonetheless wanted to determine why,” mentioned Dr. Cubillos-Ruiz, who can be co-leader of the Most cancers Biology Program within the Sandra and Edward Meyer Most cancers Heart at Weill Cornell Medication.
Working with collaborators, the researchers used a battery of biochemical assays to determine proteins that bind to FABP5. They discovered a protein known as Transgelin 2 that interacts with FABP5 and helps transfer it to the cell floor.
Additional 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 situations throughout the tumor, represses the gene encoding Transgelin 2. With out 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 basic mechanism labored out, the group explored an immunotherapy known 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 nicely in opposition to hematological cancers like leukemia and lymphoma, however they’re actually not efficient for stable tumors like ovarian or pancreatic cancers,” Dr. Cubillos-Ruiz mentioned.
When Dr. Hwang and his colleagues examined CAR T cells, that are at the moment 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. Identical to regular T cells within the tumor microenvironment, the engineered CAR T cells had FABP5 tangled within the cytoplasm. In consequence, the CAR T cells had been unable to entry lipids for vitality to successfully assault the tumor, highlighting a important barrier in utilizing this immunotherapy for stable 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 elements, so expression of the important protein was preserved. This allowed Transgelin 2 to chaperone FABP5 to the floor of the CAR T cells the place it may take up lipids.
Certainly, the upgraded T cells had been way more efficient in attacking ovarian tumors than the unique CAR T cells. “Our findings reveal a key mechanism of immune suppression in ovarian most cancers and recommend new avenues to enhance the efficacy of adoptive T cell immunotherapies in aggressive stable malignancies,” Dr. Cubillos-Ruiz mentioned.
Reference: “Transgelin 2 guards T cell lipid metabolism and antitumour operate” 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 Music and Juan R. Cubillos-Ruiz, 23 October 2024, Nature.
DOI: 10.1038/s41586-024-08071-y
This work was supported partly by the Nationwide Institutes of Well being grants R01 NS114653, CA271619, CA282072, R01 CA237154 and R01 CA269382, the U.S. Division of Protection grants W81XWH2010191, W81XWH-16-1-0438, W81XWH-22-OCRP-IIRA, W81XWH2110478 and W81XWH2110357, and the American Affiliation for Most cancers Analysis; AACR-Bristol Myers Squibb Immuno-Oncology Analysis Fellowship.