Leucine Dieting Inhibits Immunosuppressive B Cells in Colorectal Cancer

Various populations of immune cells within the tumor microenvironment can influence tumor development by promoting or inhibiting an antitumor immune response. Previous studies have proposed that a subpopulation of infiltrating immune cells known as regulatory B cells can hinder antitumor immunity, but mechanisms by which these cells impact tumor progression are not completely understood. To address this, Wang, Lu, Lin, and colleagues performed single-cell RNA-sequencing analysis of local immune cells in a carcinogen-induced murine model of colorectal cancer (CRC) and uncovered a cluster of plasmablast-like B cells, characterized by high expression of mitochondrial leucyl-tRNA synthetase (Lars2) and transforming growth factor β1 (Tgfb1). Unlike the majority of B cells localized in tertiary lymphoid structures, Lars2-expressing B (LARS B) cells were primarily found within the tumor stroma and relied heavily on leucine uptake. In agreement with the in vitro observation that supplying B cells with increasing concentrations of leucine enhanced LARS B-cell generation as well as TGFβ1 secretion, a leucine-rich diet increased the proportion of LARS B cells and accelerated tumor growth in multiple murine CRC models. Lars2 depletion in B cells reversed these leucine-induced phenotypes while inhibiting the TGFβ1-mediated differentiation of CD4⁺ T cells into immunosuppressive regulatory T cells. Since LARS2 facilitates mitochondrial protein translation of genes including subunits of the electron transport chain, changes in mitochondrial function and energy metabolism were assessed, revealing that Lars2 deletion in B cells repressed expression of NADH dehydrogenase, decreasing the NAD⁺/NADH ratio and subsequently limiting the activity of NAD⁺-consuming enzymes such as the deacetylase sirtuin 1 (SIRT1). Lars2 depletion hindered the ability of SIRT1 to deacetylate and enhance activity of the transcription factor PAX5, thereby preventing PAX5-mediated Tgfb1 expression. Furthermore, tumor-bearing mice were administered a leucine-deficient diet that inhibited tumor growth, LARS B-cell generation, and TGFβ1 secretion. Together, this work describes a mechanism by which regulatory B cells rely on amino acid metabolism to suppress antitumor immunity in CRC.

Wang Z, Lu Z, Lin S, Xia J, Zhong Z, Xie Z, et al. Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion. Immunity 2022;55:1067–81.e8.

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