Tumor-derived lactic acid modulates activation and metabolic status of draining lymph node stroma

Riedel, Angela and Helal, Moutaz and Pedro, Luisa and Swietlik, Jonathan J. and Shorthouse, David and Schmitz, Werner and Haas, Lisa and Young, Timothy and da Costa, Ana S.H. and Davidson, Sarah and Bhandare, Pranjali and Wolf, Elmar and Hall, Benjamin A. and Frezza, Christian and Oskarsson, Thordur and Shields, Jacqueline D. (2022) Tumor-derived lactic acid modulates activation and metabolic status of draining lymph node stroma. Cancer Immunology Research, 10 (4). pp. 482-497. ISSN 2326-6074 (https://doi.org/10.1158/2326-6066.CIR-21-0778)

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Communication between tumors and the stroma of tumordraining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization.