T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins

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 47 in bowel, cutaneous leukocyte antigen (CLA) in skin, nor integrin 41 or receptor CXCR3 in metastatic sites. Retention integrins E7, 11 and 21 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, 41 and CXCR3 on intratumoral endothelium. What's new? T cells are guided to inflamed tissues by cell-surface receptors, a process well characterized for noncancerous conditions. But T-cell homing also plays an important role in malignant disease, such as in metastatic melanoma, where T-cell infiltration may benefit survival. This study of the metastatic melanoma microenvironment implicates the cell-surface receptor CC9 in T-cell homing to the bowel. Other site-specific homing molecules were found to be of limited relevance in human melanoma metastases. However, elevated expression of integrins 11, 21, E7 was observed in metastases, suggesting that retention integrins may be vital to maintaining intratumoral T cells.