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

Communication between tumors and the stroma of tumor draining lymph nodes (TDLNs) exists before metastasis arises, altering structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRCs), the dominant stromal population of the LN, revealed reprogramming of these cells in immune related pathways, but also in fibroblast activation and mitochondrial function. However, tumor derived factors driving the changes in FRCs remained to be identified. Taking an unbiased approach, we show that lactic acid (LA), a metabolite released by cancer cells, is not only secreted by B16.F10 and 4T1 tumors in high amounts, but that it is also enriched in TDLNs. LA supports an upregulation of 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 show that tumor-derived LA alters mitochondrial function of FRCs of TDLNs. Thus, our results demonstrate a novel mechanism by which a tumor-derived metabolite connected with a low pH environment modulate the function of fibroblasts in TDLNs. RNA sequencing