THE ROLE OF GAMMA-DELTA (γδ) T LYMPHOCYTES IN MELANOMA: BASIC SCIENCE FINDINGS AND CLINICAL CORRELATIONS

Abstract

INTRODUCTION: Advanced melanoma is associated with a poor prognosis. Numerous clinical trials have focused on the potential of tumor-infiltrating lymphocytes (TILs) for immunotherapy in stage III and IV melanoma, but its treatment remains challenging. Gamma-delta (γδ) T cells are the most represented subpopulation of TILs and have shown therapeutic potentials in many solid tumors, although their role against melanoma has not been fully investigated. MATERIALS AND METHODS: Seventy-four patients with cutaneous melanoma underwent peritumoral skin biopsies and blood sample collection. TILs and circulating lymphocytes phenotype and effector functions were analzyed using immunohistochemistry and flow citometry. Blood samples from 8 healthy subjects were used as control. In vitro cytotoxicity assays on γδ T cells were performed using melanoma cell lines pre-treated and not pre-treated with zoledronate. Mortality and relapsed rates were recorded over a mean follow-up period of 29 months (range 12-48). RESULTS: Γδ T lymphocytes were isolated in 62% of skin biopsies and represented the predominant population of TILs, with a significant difference between stage 0-II (71.9%) and stage III-IV (29.4%). A significantly higher number of effector peripheral γδ T cells were found compared to controls (27.7% vs 20%, p<0.05), despite a similar absolute γδ T cell number. Both TILs and circulating lymphocytes showed a predominant effector memory phenotype (40%) and a strong cytotoxic capacity toward melanoma cells enhanced after in vitro stimulation with zoledronate. Isolation of peripheral γδ T cells inversely correlates withmortality and relapse rates in metastatic melanoma (0% vs 50% and 13% vs 32.1% respectively). CONCLUSIONS: Our data suggests that γδ T cells may play a pivotal role in the antitumoral response against melanoma, which significantly decreases in the advanced disease. They display a strong in vitro cytotoxicity and should be regarded as prominent target cells for enhancing antitumor response in advanced melanoma. Their striking in vitro response to stimulation with zoledronate may prompt further in vivo investigation and innovative immunotherapeutic approaches.