Tumor Induced Stromal Reprogramming Drives Lymph Node Transformation

Lymph node (LN) stromal cells, particularly fibroblastic reticular cells (FRCs), provide critical structural support and regulate immunity, tolerance and transport properties of LNs. In many tumors, LN metastasis is predictive of poor prognosis. However, the stromal contribution to the evolving microenvironment of tumor draining LNs (TDLNs) remains poorly understood. Here we show that FRCs specifically of TDLNs proliferate in response to tumor-derived cues and that the network they form is remodeled. Comparative transcriptional analysis of non-draining and TDLN FRCs demonstrated reprogramming of key pathways including matrix remodeling, chemokine/cytokine signaling and immune functions including leukocyte recruitment, migration and activation. In particular, downregulation of FRC-derived CCL21 and IL-7 were accompanied by altered immune composition and aberrant localization. These data imply that stroma of TDLNs adapt on multiple levels, following exposure to tumor-derived factors, to exhibit features typically associated with immune suppression.