J Immunother Cancer. 2022 Dec;pii: e005644. [Epub ahead of print]10(12):
Nobuhiko Imahashi,
Rafet Basar,
Yuefan Huang,
Fang Wang,
Natalia Baran,
Pinaki Prosad Banerjee,
Junjun Lu,
Ana Karen Nunez Cortes,
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 Lorraine Wei Inng Lim,
Hila Shaim,
Ye Li,
Marina Konopleva,
Michael Green,
Jennifer Wargo,
Elizabeth J Shpall,
Ken Chen,
Katayoun Rezvani.
BACKGROUND: B 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.METHODS: We 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.
RESULTS: Here 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.
CONCLUSIONS: We 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.
Keywords: B-lymphocytes; T-lymphocytes; immunomodulation; immunotherapy; melanoma