Lactate blocks tertiary lymphoid structure formation by inhibiting B cell chemotaxis
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Victoire Boulat Elena Alberts Paul Driscoll Miu Shing Hung Ana Cunha Jelmar Quist Fangfang Liu Carin Andrea Brundin Ananya Bhalla Lidia Avalle James Rosekilly Lucy Ryan Cheryl Gillett Molly Strom Valeria Poli James MacRae Anita Grigoriadis Dinis CaladoThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. Using fractionation and metabolic profiling, we identify lactate as a dominant tumor-secreted metabolite that directly impairs B cell chemotaxis by disrupting mitochondrial metabolism. In vivo, combining lactate inhibition with engineered chemokine secretion promotes cLN-derived B cell infiltration and enables TLS formation, particularly when coupled with CD40 stimulation. Transcriptomics analyses across several human cancer datasets strengthen the association between high glycolytic activity with poor B-cell infiltration in chemokine-rich tumors. Together, our findings reveal lactate as a key metabolic barrier to B cell trafficking and TLS induction, suggesting that metabolic reprogramming may provide an avenue to convert “immune-cold” tumors into TLS-rich, immunologically responsive microenvironments.
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bioRxiv
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