Ovarian cancer lessens efficacy of T-cell immunotherapy, study finds
Tumors work to trap a protein needed for energy by CAR T-cells in a therapy
The microenvironment of ovarian cancer tumors actively suppress the work of immune T-cells by blocking their energy supply, a study reports.
These findings have implications for T-cell immunotherapies, such as CAR T-cell therapy, which have limited efficacy against solid tumors such as ovarian cancer, the researchers, at Weill Cornell Medicine in New York, noted.
When tested in a mouse model, a CAR T-cell therapy currently in a clinical trial in advanced ovarian cancer patients showed similar energy defects. Preventing the tumor-induced blockade of T-cell energy enhanced the immunotherapy’s tumor-killing properties.
“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,” Juan Cubillos-Ruiz, PhD, an associate professor of infection and immunology at Weill Cornell, said in a university news story.
Details of the discovery were in the study “Transgelin 2 guards T cell lipid metabolism and antitumour function,” published in the journal Nature.
T-cell immunotherapies show less efficacy in ovarian, pancreatic cancers
T-cell immunotherapies are a promising approach for cancer treatment. CAR T-cell therapy is one such approach, whereby a patient’s T-cells are collected and modified in the lab to produce a receptor called a chimeric antigen receptor (CAR) that recognizes a specific anti-cancer target. Upon infusion, these modified T-cells attack and destroy cancer cells.
While such T-cell-based immunotherapies have shown promise in cancers of blood cells, they aren’t as effective against solid tumors, including ovarian cancers. Research indicates that T-cells infiltrating ovarian tumors become dysfunctional and lose their ability to fight cancer.
“CAR T cells work well against [blood] cancers like leukemia and lymphoma, but they’re really not effective for solid tumors like ovarian or pancreatic cancers,” said Cubillos-Ruiz, who is also co-leader of the cancer biology program at Weill Cornell.
Cytotoxic T-cells, also called CD8-positive cells, are a type of T-cell used in immunotherapies, and they rely on fatty acids (lipids) as an energy source. FABP5 is a protein that drives this process by facilitating the import of fatty acids into T-cells to be converted to energy within the cell’s mitochondria — the powerhouse of cells.
However, it’s unknown whether ovarian cancers disrupt the FABP5-mediated metabolism of fatty acids in T-cells to evade immune responses.
“T cells rely on lipids as fuel, burning them in their mitochondria to power their fight against pathogens and tumors,” Cubillos-Ruiz said. “However, the molecular mechanisms that govern this critical energy supply are still not well understood.”
Cytotoxic T-cells in ovarian cancers are denied necessary energy
To investigate, the researchers collected cytotoxic T-cells from the solid tumors and blood of women with high-grade serous carcinoma, the most common type of ovarian cancer. Experiments confirmed problems in the uptake of fatty acids in these T-cells, compared with those from women without cancer.
Because the fatty acid uptake defect was accompanied by a 50% drop in FABP5 production but not in other lipid transporters, they proposed that ovarian cancer might alter the localization and/or activity of FABP5. Indeed, in patient-derived tumor samples and mouse models of ovarian cancer, FABP5 became trapped inside the T-cells instead of moving to the cell surface, where it typically would be to import fatty acids.
“That was the ‘aha!’ moment; since FABP5 is not getting to the surface, it couldn’t bring in the lipids necessary for energy production,” Cubillos-Ruiz said. “But we still needed to figure out why.”
Using a battery of biochemical tests, the researchers identified a protein called transgelin-2 that interacts with FABP5 and helps it move to the cell surface.
Although increased production of this protein has been documented in certain cytotoxic T-cells during viral infection, transgelin-2 was seen to be suppressed in infiltrating T-cells in ovarian tumors. Experiments also revealed that the stressful conditions within the tumor activate XBP1, another protein that blocks the activity of the TAGLN2 gene that guides transgelin-2 production.
Based on these findings, the researchers suggested that the tumor-induced suppression of transgelin-2 may restrict the therapeutic effects of CAR T-cells in ovarian cancer.
Modified CAR T-cells showed greater ability to target tumors in mice
To test this, they treated a mouse model of metastatic ovarian cancer with a CAR T-cell therapy being used in a clinical trial in advanced ovarian cancer patients (the Phase 1 study NCT05316129 was noted by the scientists). Like the T-cells in the tumor microenvironment, transgelin-2 in these CAR T-cells was repressed, trapping the FABP5 protein inside the cells and disrupting fatty acid uptake and cellular energy.
When the scientists then gave the mice CAR T-cells containing a modified version of the TAGLN2 gene that couldn’t be blocked by XBP1, transgelin-2 successfully brought FABP5 to the surface of the CAR T-cells. There, it increased fatty acid uptake and enhanced the cells’ tumor-killing properties relative to the original CAR T-cells.
“Adoptive immunotherapy using unmodified … T cells failed to extend survival in mice developing these aggressive tumours. By contrast, treatment with … [the modified] T cells significantly prolonged the survival of mice with metastatic disease,” the researchers wrote.
“These findings reveal a crucial immunosuppressive mechanism in the [tumor microenvironment] and a potential approach to improve the efficacy of T cell-based immunotherapies in solid malignancies,” they concluded.
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