Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors
(1) Lontos K (2) Wang Y (3) Joshi SK (4) Frisch AT (5) Watson MJ (6) Kumar A (7) Menk AV (8) Wang Y (9) Cumberland R (10) Lohmueller J (11) Carrizosa E (12) Boyerinas B (13) Delgoffe GM
(1) Lontos K (2) Wang Y (3) Joshi SK (4) Frisch AT (5) Watson MJ (6) Kumar A (7) Menk AV (8) Wang Y (9) Cumberland R (10) Lohmueller J (11) Carrizosa E (12) Boyerinas B (13) Delgoffe GM
Background: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors. We and others have shown the tumor microenvironment harbors a distinct metabolic landscape that produces a barrier to immune cell function. Further, altered differentiation of T cells within tumors induces defects in mitochondrial biogenesis, resulting in severe cell-intrinsic metabolic deficiencies. While we and others have shown murine T cell receptor (TCR)-transgenic cells can be improved through enhanced mitochondrial biogenesis, we sought to determine whether human CAR-T cells could be enabled through a metabolic reprogramming approach.
Author Info:
(1) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (2) Tumor Microenvironment Center, Depart
ment of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. Tsinghua University School of Medicine, Beijing, China. (3) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (4) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (5) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (6) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (7) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (8) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. Tsinghua University School of Medicine, Beijing, China. (9) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. (10) Department of Surgery, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (11) 2seventybio, Boston, Massachusetts, USA. (12) 2seventybio, Boston, Massachusetts, USA. (13) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA delgoffeg@upmc.edu.
