title: Mesenchymal contribution to recruitment, infiltration, and positioning of leukocytes in human melanoma tissues.
abstract: To understand factors that regulate leukocyte entry and positioning within human melanoma tissues, we performed a multiparametric quantitative analysis of two separated regions: the intratumoral area and the peritumoral stroma. Using two mesenchymal markers, fibroblast activation protein (FAP) and CD90, we identified three subsets of mesenchymal cells (MCs): (i) intratumoral FAP(+)CD90(low/-) MC, (ii) peritumoral FAP(+)CD90(+) MC, and (iii) FAP(-)CD90(+) perivascular MC. We characterized CD90(+) MCs, which showed a stable CCL2-secretory phenotype when long-term expanded ex vivo, and heavily surrounded peritumoral Duffy antigen receptor for chemokine(+) (DARC) postcapillary venules, supporting a role for these vessels in peritumoral inflammatory leukocyte recruitment. Conversely, the intratumoral area was variably invaded by FAP(+)CD90(low/-) MCs that colocalized with a distinct extracellular matrix (ECM) network. A positive correlation was observed between intratumoral stromal cell/ECM networks and leukocyte infiltration among tumor cells (TCs), as well as in a stroma-dependent xenograft tumor model. Adoptively transferred T lymphocytes preferentially infiltrated tumors composed of TC+MC, compared with TCs only. Altogether, our results suggest that a variety of MCs contribute to regulate different steps of leukocyte tumor infiltration, that is, CD90(+) cells surrounding peritumoral vessels secrete CCL2 to recruit CCR2(+) leukocytes at the tumor periphery, whereas intratumoral FAP(+) cells organize a stromal scaffold that contact guide further invasion among densely packed tumor cells.
authors: Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors: Rafael
authors: R
authors: Samaniego
authors: Ana
authors: A
authors: Estecha
authors: Miguel
authors: M
authors: Relloso
authors: Natividad
authors: N
authors: Longo
authors: José L
authors: JL
authors: Escat
authors: Isabel
authors: I
authors: Longo-Imedio
authors: José A
authors: JA
authors: Avilés
authors: Miguel A
authors: MA
authors: del Pozo
authors: Amaya
authors: A
authors: Puig-Kröger
authors: Paloma
authors: P
authors: Sánchez-Mateos
mesh_terms: D000818:Animals; D001706:Biopsy; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000473:pathology*; D008545:Melanoma / Q000098:blood supply / Q000276:immunology / Q000556:secondary*; D008648:Mesoderm / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D054390:Receptors, CCR2 / Q000276:immunology; D012878:Skin Neoplasms / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2