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

Francesca Toia,Francesco Moschella,Serena Meraviglia,Simona Buccheri,Adriana Cordova,Ampelio Anfosso,Francesco Dieli,Hiroshi Shiku

doi:10.1371/journal.pone.0149570

Francesca Toia, Francesco Moschella + Show 6 more

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https://doi.org/10.1371/journal.pone.0149570

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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.

Highlights

Malignant melanoma accounts for only 3% of cutaneous tumors, but shows high tendency to metastasize and is responsible for as much as 65% of death for skin cancers [1]
Mean 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

Summary

Introduction

Malignant melanoma accounts for only 3% of cutaneous tumors, but shows high tendency to metastasize and is responsible for as much as 65% of death for skin cancers [1]. In the last 40 years, increasing interest has developed toward host cellular immune response and its possible therapeutic implication in the adjuvant therapy and advanced disease settings. Spontaneous regression of disease has been reported in patients with melanoma, suggesting a role for host immunity [5], which is indirectly supported by the evidence for lymphocyte infiltration of primary melanomas associated with tumor regression [6,7]. Tumor-infiltrating lymphocytes (TILs) have been shown to play an important role in the anti-tumor surveillance and have been documented in a wide variety of solid tumors including melanoma, breast, renal cell, prostate and colon cancers [8,9,10]. Increasing evidence exists for a role of γδ T lymphocytes in the anti-tumor surveillance in the periphery [21], which is supported by their localization within epithelia. There is a substantial interest in γδ T cells in the context of immunotherapeutic strategies and several pilot studies have described a partial success of γδ T cellbased immunotherapy in different types of cancer after the application of aminobisphosphonates (n-BP) or PAgs plus IL-2 in vivo or after repetitive transfer of in vitro expanded Vγ9Vδ2 T cells [27,28]

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