Reprogramming glutamine metabolism enhances <i>BCMA</i> -CAR T-cell fitness and therapeutic efficacy in multiple myeloma
Abstract
Abstract Glutamine dependence of cancer cells reduces local glutamine availability, which hinders antitumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of chimeric antigen receptor (CAR) T-cell therapies in patients with cancer. We have seen that antigen-specific T cells are unable to proliferate or produce interferon gamma (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 B-cell maturation antigen (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 the metabolic fitness of CAR T cells by upregulating the mechanistic target of rapamycin complex 1 gene signature, modifying the solute carrier transporter repertoire, and improving both basal oxygen consumption rate and glycolytic function, thereby enhancing CAR T-cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of Bcma-CAR T cells in syngeneic and genetically engineered mouse models of MM, which prolonged mouse survival. In patients, higher-level 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 antitumor 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.
Article Details
Authors (26)
Flor Navarro
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Teresa Lozano
Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain
Andrea Fuentes-García
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Inés Sánchez-Moreno
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Marta Larrayoz
Pedro Justicia
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Beatriz Perucha
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Maialen Martinez-Tabar
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Rebeca Martinez-Turrillas
2Hemato-Oncology Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Noelia Casares
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Celia Martín-Otal
Marta Gorraiz
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Erin W. Meermeier
1Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ
Marta Chesi
Douglas Lake
5School of Life Sciences, Arizona State University, Phoenix, AZ
P. Leif Bergsagel
Mayo Clinic Arizona, Scottsdale
Eva Santamaría
6RNA Biology and Therapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, University of Navarra, Pamplona, Spain
Maria Erendira Calleja-Cervantes
Patxi San Martín-Uriz
1Center for Applied Medical Research, Universidad de Navarra, Navarra Medical Research Institute, Pamplona, Spain
Lorea Jordana-Urriza
2Hemato-Oncology Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Xabier Agirre
Sandra Hervás-Stubbs
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Juan Roberto Rodriguez-Madoz
1Center for Applied Medical Research, Universidad de Navarra, Navarra Medical Research Institute, Pamplona, Spain
José Ángel Martinez-Climent
2Hemato-Oncology Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain
Felipe Prosper
Juan José Lasarte
1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain