Qiu et al. identified impaired mannose metabolism to be a common feature of T cell dysfunction in human cancer (multiple tumor types), mouse liver cancer, and LCMV infection. Enhancing mannose metabolism by D-mannose treatment of adoptively transferred T cells resulted in multiple metabolic and epigenetic changes, such as increased generation of stem-like T cells, reduced T cell differentiation to exhaustion, and increased antitumor efficacy and survival. Mechanistically, D-mannose increased O-GlcNAc transferase-mediated O-GlcNAcylation and stabilization of β-catenin, preserving Tcf7 expression and epigenetic stemness, even after extensive long-term culture.
Contributed by Katherine Turner
ABSTRACT: Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of _-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8(+) T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, J
Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (2) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Departments of Immunology and Medicine, University of Washington, Seattle, WA 98109, USA; Herbold Computational Biology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (3) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (4) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (5) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (6) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (7) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (8) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. (9) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Departments of Immunology and Medicine, University of Washington, Seattle, WA 98109, USA; Herbold Computational Biology Program, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215123, Jiangsu, China. (11) Program in Immunology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Departments of Immunology and Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: pgreen@u.washington.edu. (12) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China; Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China. Electronic address: lgd@ism.cams.cn.
