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 (TIN), skin, and small bowel) were evaluated by multiparameter flow cytometry and compared to benign lymph nodes (NLN) and peripheral blood mononuclear cells (PBMC) 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 did not 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.

Very Late Antigen-1 Marks Functional Tumor-Resident CD8 T Cells and Correlates with Survival of Melanoma Patients

“…We then investigated the expression of those analytes on CD8 + T cells derived from metastatic lesions from various organs including skin, lung, and brain. While we did not observe significant expression of P-selectin ligands by CD8 + TIL, we saw specific enrichment for cells expressing VLA-1, consistent with previous reports in melanoma bowel metastases (30) and head and neck tumors (31). Moreover, co-expression of VLA-1 together with CD69 and CD103, the archetypal markers of T RM differentiation, was observed on a large proportion of cells that infiltrate tumors.…”

Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma

“…Several studies have provided indication that the subset of DCs is infiltrating upon a CCR5-dependent chemokine signal (10,23). In fact, we and others have observed a highly significant correlation between the degree of T-cell infiltration and the predominantly tumor cell-derived expression of CCL3, CCL4, and CCL5, all chemokines binding to the CCR5 receptor, suggesting a potentially strong correlation between chemokine suppression, lack of DC infiltration, and thereby mediated lack of T-cell infiltration (8,10,24). We also evaluated whether tumor cell-intrinsic activation of Wnt/β-catenin signaling or loss of PTEN, both previously reported to affect accumulation or activation of DCs, might be associated with a skewed neoantigen profile in the HLA-A*0201-positive patients.…”

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells

“…While trafficking to peripheral tissue may be driven by inflammatory signals, the retention and accumulation of T RM within peripheral tissues may depend on continued presence of antigen within the tissue site (36). In addition, the capacity of T cells to infiltrate or remain within individual tissues may also depend on the expression of specific chemokines or retention integrins, which in turn may affect immune control of tumors (37)(38)(39).…”