Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+ CD11b+HLA-DR- MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy. Experimental Design: Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR- MDSC percentage, NO- hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS). Results: Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR- MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR- cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months. Conclusions: Our study suggests the use of CD33+ CD11b+HLA-DR- cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes.
Bibliographical noteFunding Information:
This work was supported by the Israel Science Foundation (ISF), Joint Program between the Israel Science Foundation (ISF) and the National Natural Science Foundation of China (NSFC), the Israeli Ministry of Health, the Joint German-Israeli Research Program (DKFZ-MOST), the Israel Cancer Research Fund (ICRF), the NOFAR, industrial application of Academic Research Office of the Chief Scientist, Ministry of Economy, and the Joseph and Matilda Melnick Funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
© 2016 American Association for Cancer Research.