Activated B cells suppress T-cell function through metabolic competition

• DOI: 10.1136/jitc-2022-005644
• Publication Date: 2022-12-21T15:48:34Z
• Authors: Nobuhiko Imahashi; Rafet Basar; Yuefan Huang; Fang Wang; Natalia Baran; Pinaki Prosad Ban...; Junjun Lu; Ana Karen Nunez C...; Nadima Uprety; Emily Ensley; Luis Muniz-Feliciano; Tamara J Laskowski; Judy S Moyes; May Daher; Mayela Mendt; Lucila N Kerbauy; Mayra Shanley; Li Li; Francesca Lorrain...; Hila Shaim; Ye Li; Marina Konopleva; Michael Green; Jennifer Wargo; Elizabeth J Shpall; Ken Chen; Katayoun Rezvani
• Keywords: Sirolimus; 0301 basic medicine; B-Lymphocytes; Medical Sciences; Biochemical Phenomena; Bioinformatics; T-Lymphocytes; Life Sciences; 610; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Basic Tumor Immunology; Biomedical Informatics; 3. Good health; 03 medical and health sciences; Metabolism; Oncology; Medical Specialties; Medicine and Health Sciences; Immunotherapy; RC254-282; Immunosuppressive Agents; and Nutrition; Immunology and Infectious Disease

BackgroundB cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood.MethodsWe investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing.ResultsHere we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell–cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy.ConclusionsWe have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.