Skewed Differentiation of Circulating Vγ9Vδ2 T Lymphocytes in Melanoma and Impact on Clinical Outcome

Abstract

ObjectiveThe aim of this study was to evaluate over time circulating γδ T lymphocytes in melanoma patients in terms of frequency, effector functions, and relationship with clinical stage and evolution, by comparing preoperative values to those obtained at a mean follow-up of 36 months or in the event of recurrence or disease progression, and to those of healthy controls. Also, we correlated the presence of tumor-infiltrating γδ T lymphocytes with clinical evolution of melanoma.ResultsMean frequencies of circulating γδ T cells before and after melanoma removal were very similar and comparable to healthy subjects, but patients who progressed to stage III or IV showed a significantly decreased frequency of circulating Vγ9Vδ2 T cells. The distribution of Vγ9Vδ2 memory and effector subsets was similar in healthy subjects and melanoma patients at diagnosis, but circulating γδ T cells of patients after melanoma removal had a skewed terminally-differentiated effector memory phenotype. Highly suggestive of progressive differentiation toward a cytotoxic phenotype, Vγ9Vδ2T cells from patients at follow up had increased cytotoxic potential and limited cytokine production capability, while the opposite pattern was detected in Vγ9Vδ2T cells from patients before melanoma removal.ConclusionsFollow-up data also showed that tumor infiltrating γδ T cells were significantly associated with lower mortality and relapse rates, suggesting that they may serve as a prognostic biomarker, for human melanoma.

Human Peripheral Blood Gamma Delta T Cells: Report on a Series of Healthy Caucasian Portuguese Adults and Comprehensive Review of the Literature

“…As for αβ Tc, there are many factors influencing the immunophenotypic features of γδ Tc. Upon stimulation, naïve γδ Tc can sequentially differentiate into T CM , T EM and T EMRA cells, thereby modifying the levels of CD45RA, CD45RO, CD27, CD28, CD197/CCR7 and other cell surface receptors [72,163,164]. In addition, once activated, γδ Tc modulate a wide range of cell surface activation-related molecules (e.g., CD69, CD25, CD28, CD38, CD45RO and HLA-DR) [165,166].…”

Nano-technology based carriers for nitrogen-containing bisphosphonates delivery as sensitisers of γδ T cells for anticancer immunotherapy

“…Infiltration of γδ T cells has been reported in many different tumour types including melanoma, ovary, colon, lung and prostate [123]. In melanoma patients, tumour infiltrating γδ T cells were significantly associated with lower mortality and relapse rates [124]. Additionally, patients who progressed to stage III or IV melanoma had a significantly decreased frequency of circulating Vγ9Vδ2 T cells.…”

Lymphocyte-mediated Immune Regulation in Health and Disease: The Treg and γδ T Cell Co-conspiracy

“…For instance, γδ T cells have demonstrated cytotoxic function against colon cancer and myeloma cells, (Wu et al 2015, von Lilienfeld-Toal et al 2006). Additionally, recent studies have suggested a cytotoxic role for Vδ9Vγ2 T cells in patients with melanoma; wherein an elevated frequency of circulating as well as tumor infiltrating Vδ9Vγ2 T cells in early stage tumors were correlated with decreased mortality and disease relapse (Toia et al 2016). Interestingly, however, it was observed that melanoma patients with a poor prognosis possessed a dramatically increased frequency of tumor-infiltrating Vδ9Vγ2 T cells in late stage disease.…”

“…Interestingly, however, it was observed that melanoma patients with a poor prognosis possessed a dramatically increased frequency of tumor-infiltrating Vδ9Vγ2 T cells in late stage disease. While no functional studies were performed, such observations may represent the acquisition of a suppressive phenotype due to modulation of the tumor microenvironment (Toia et al 2016). …”