Despite recent breakthroughs in cancer immunotherapy, T-cell based therapies achieve limited efficacy in solid tumors. Immunosuppression, antigen escape and physical barriers to entry into solid tumors are issues faced. Identifying regulators in T-cell dysfunction remains challenging due to limitations of current screening platforms.
Using single-cell transcriptomic data from tumors as input, researchers at the National Cancer Institute’s Cancer Data Science Laboratory developed a computational model of T-cell resilience called “Tres” to search for gene markers of T cells that allow T cell proliferation in the immunosuppressive tumor microenvironments. Integrating 36 single-cell transcriptomic cohorts, covering 168 tumors from 19 tumor types, researchers identified acidic fibroblast growth factor intracellular-binding protein (FIBP) as a top regulator of T-cell resilience. Knocking out FIBP in murine and human donor T cells significantly enhanced the efficacy of T-cell mediated killing of in vitro cancer cell lines and adoptive cell therapy in a mouse model. Mechanistically, FIBP knockout in CD8 lymphocytes alleviated T-cell dysfunction by limiting cholesterol metabolisms, a recognized factor to inhibit T-cell activity. In summary, targeting FIBP in T cells is a novel approach to enhance the efficacy of adoptive cell therapy in solid tumors.
The National Cancer Institute seeks partners to license and/or co-develop this technology towards commercialization.
- FIBP knockdown/knockout inhibits cell proliferation
- FIBP knockdown/knockout enhances chemotherapy effects
- FIBP knockdown/knockout attenuates stemness markers
- Solid cancers previously non-responsive to T cell-based immunotherapy
- Tres can identify biomarkers of response to immunotherapy
- Tres can identify new targets for therapeutic intervention