title: Tumor-induced stromal reprogramming drives lymph node transformation.
abstract: Lymph node (LN) stromal cells, particularly fibroblastic reticular cells (FRCs), provide critical structural support and regulate immunity, tolerance and the transport properties of LNs. For many tumors, metastasis to the LNs is predictive of poor prognosis. However, the stromal contribution to the evolving microenvironment of tumor-draining LNs (TDLNs) remains poorly understood. Here we found that FRCs specifically of TDLNs proliferated in response to tumor-derived cues and that the network they formed was remodeled. Comparative transcriptional analysis of FRCs from non-draining LNs and TDLNs demonstrated reprogramming of key pathways, including matrix remodeling, chemokine and/or cytokine signaling, and immunological functions such as the recruitment, migration and activation of leukocytes. In particular, downregulation of the expression of FRC-derived chemokine CCL21 and cytokine IL-7 were accompanied by altered composition and aberrant localization of immune-cell populations. Our data indicate that following exposure to tumor-derived factors, the stroma of TDLNs adapts on multiple levels to exhibit features typically associated with immunosuppression.
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Riedel
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Shorthouse
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Haas
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hall
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Shields
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D065150:Cellular Reprogramming; D054421:Chemokine CCL21 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D015851:Interleukin-7 / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D017154:Stromal Cells / Q000502:physiology*; D046888:Tissue Array Analysis; D059467:Transcriptome; D059016:Tumor Microenvironment
chemical_list: D054421:Chemokine CCL21; D016207:Cytokines; D015851:Interleukin-7