Clinical significance of circulating CD33⁺ CD11bHLA-DR myeloid cells in patients with stage IV melanoma treated with ipilimumab

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.