title: T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins.
abstract: T-cell infiltration into the metastatic melanoma microenvironment (MME) correlates with improved patient survival. However, diffuse infiltration into tumor occurs in only 8% of melanoma metastases. Little is known about mechanisms governing T-cell infiltration into human melanoma metastases or about how those mechanisms may be altered therapeutically. We hypothesized that T cells in the MME would be enriched for chemokine receptors CCR4, CCR5, CXCR3 and homing receptors relevant to the tissue site. Viably cryopreserved single cell suspensions from nineteen melanoma metastases representing three metastatic sites (tumor-infiltrated lymph node, skin and small bowel) were evaluated by multiparameter flow cytometry and compared to benign lymph nodes and peripheral blood mononuclear cells from patients with Stage IIB-IV melanoma. T cells in the melanoma metastases contained large effector memory populations, high proportions of activated, moderately differentiated cells and few regulatory T cells. Site-specific homing was suggested in bowel, with high expression of CCR9. We neither encounter the anticipated enrichment of integrin α4β7 in bowel, cutaneous leukocyte antigen (CLA) in skin, nor integrin α4β1 or receptor CXCR3 in metastatic sites. Retention integrins αEβ7, α1β1 and α2β1 were significantly elevated in metastases. These data suggest limited tissue site-specific homing to human melanoma metastases, but a significant role for retention integrins in maintaining intratumoral T cells. Our findings also raise the possibility that T-cell homing, infiltration, and retention in melanoma metastases may be increased by increasing expression of ligands for CLA, α4β1 and CXCR3 on intratumoral endothelium.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Virginia, Charlottesville, VA.
authors.forename: Elise P
authors.initials: EP
authors.lastname: Salerno
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Chantel
authors.initials: C
authors.lastname: McSkimming
authors.forename: Sofia
authors.initials: S
authors.lastname: Shea
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
mesh_terms: D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D016023:Integrins
keywords: cancer immunology; chemokine receptor; integrin; metastatic melanoma; tumor microenvironment