https://orcid.org/0000-0001-7122-5475
Key Points
Glutamine deprivation in the tumor microenvironment might limit CAR T-cell therapeutic efficacy in cancer patients.
ASCT2 overexpression improves the metabolic fitness and antitumor efficacy of BCMA-CART for multiple myeloma treatment
Glutamine-dependence of cancer cells reduces local glutamine availability, which hinders anti-tumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of CAR T-cell therapies in cancer patients. We have seen that antigen-specific T cells are unable to proliferate or produce IFN-γ in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR-T cells selectively targeting BCMA in MM cells were sensitive to glutamine deprivation. However, CAR-T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-γ, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed CART cell metabolic fitness of CART cells by upregulating the mTORC1 gene signature, modifying the Solute Carrier transporter (SLC) repertoire, and improving both basal oxygen consumption rate and glycolytic function thereby enhancing CART cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of BCMA-CART cells in syngeneic and genetically-engineered mouse models of MM, which prolonged mouse survival. In patients, reduced expression of Asct2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance anti-tumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.
