Myeloid-Derived Suppressor Cells Predict Survival of Patients with Advanced Melanoma: Comparison with Regulatory T Cells and NY-ESO-1- or Melan-A–Specific T Cells

Abstract

Purpose: To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis.Experimental Design:Tregs, and the presence of NY-ESO-1-or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models.Results: NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of >11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P < 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs.Conclusions: Circulating CD14 þ CD11b þ HLA-DR À/low MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches.

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

“…37). In contrast with MDSCs, no prognostic role of Tregs was observed in what is thus far the largest study of patients with advanced melanoma published recently (38). Moreover, a sustained increase in the frequency and absolute count of lymphocytes (mainly of the CD4 þ T cells) and the temporary increase of NK cell count was observed here, as previously reported for IL2-based treatments (20).…”

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…[32][33][34] Moreover, the frequency of these cells in the circulation at baseline of cancer patients has been shown to act as a possible predictor of clinical outcome for IPI regimens. 32,35,36 Unfortunately, the limited availability of PBMCs from these patients prevented to evaluate the frequency of circulating Tregs and MDSCs in these MM patients; this analysis will be objective of future studies.…”

Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

“…In the course of our analysis, we used a flow cytometry test to detect CD33 þ CD11b þ HLA-DR À MDSC frequencies in whole-blood frozen samples; unlike many of the published studies, which used a Ficoll density gradient centrifugation step for peripheral blood mononuclear cells (PBMCs) preparation, before freezing the samples and evaluating MDSC frequencies (9,17,(19)(20)(21). To determine the effect of cryopreservation/thawing and Ficoll centrifugation on MDSCs as well as on T-cell frequency, blood samples from 15 HD were analyzed.…”

“…An important feature of melanoma is the induction of a strong chronic inflammatory environment, detected in the advanced stages of the disease, which is accompanied by an increased production of inflammatory factors and accumulation of suppressive immune cells such as regulatory T cells (Treg) and MDSCs (7)(8)(9).…”

“…Indeed, recent studies have shown that circulating CD14 þ CD11b þ HLA-DR À/low monocytic MDSC, but not Tregs could be used as prognostic biomarkers for predicting survival rates in patients with advanced melanoma (9) and that increased levels of this unique monocytic MDSC population correlates with lack of response in patients with melanoma treated with anti-CTLA4 therapy (19,20). However, whether high levels of the global population of MDSCs, CD33 þ CD11b þ HLA-DR À , containing both the granulocytic and monocytic subpopulations also correlate with lack of response and short-term survival in patients treated with anti-CTLA4 remains an open question.…”