Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway

Abstract

Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7 + CD56 bright NK cells as well as high serum concentrations of the CCR7-ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7 + melanoma cell subpopulation co-expressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSCs) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7 + , PD-L1 + and Galectin-9 + melanoma cells in melanoma metastases was demonstrated ex vivo. Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.

New avenues for melanoma immunotherapy: Natural Killer cells?

“…Furthermore, CCR7 + melanoma cells were particularly enriched in metastatic lesions, suggesting an immunoescape axis involving CCR7-CCL19 resulting in altered NK cell homing. 93 A similar increase in the frequency of peripheral CD56 bright NK cells correlating with disease stage has been reported in thyroid cancer patients. In this setting, CD56 bright NK cells have been shown to express both Tim-3 and PD-1, whose levels increased with disease severity.…”

“…Perturbations in the relative proportions of the two main human NK cell subsets have also been reported . CD56 bright NK cell subset is predominant within secondary lymphoid organs, while it is poorly represented in the circulation.…”

“…The same molecules also were expressed by human melanoma cells, together with the inhibitory ligands PD‐L1 and Galectin‐9. Furthermore, CCR7 + melanoma cells were particularly enriched in metastatic lesions, suggesting an immunoescape axis involving CCR7‐CCL19 resulting in altered NK cell homing …”

CCL19 has potential to be a prognostic biomarker and a modulator of tumor immune microenvironment (TIME) of breast cancer: a comprehensive analysis based on TCGA database

“…CCL19 was signi cantly associated with the survival and speci c clinic-pathological features of BC patients CCL19, a ligand of the chemokine receptor C-C chemokine receptor type 7 (CCR7), is often expressed in the T-cell zones, including lymph nodes and thymus [12] . Recently, researches revealed that the overexpression of CCL19 in serum was associated with the progression of melanoma [13,14] . In addition, CCL19 functioned as an immune-modulator for colon cancer therapy by closely communicating with DCs, T cells and B cells, thus regulating the adaptive immune responses [15] .…”

Microbes, immunity and cancer in Capri: Another successful course of the EFIS‐EJI Ruggero Ceppellini Advanced School of Immunology founded by Serafino Zappacosta

“…She reviewed the evidence that NK cells recognize target cells in a complementary way to cytotoxic T cells and that they are particularly effective against cancer stem cells. In addition, certain surface markers on NK cells can serve as biomarkers to assist cancer immunotherapies, particularly for solid tumours .…”