title: Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab.
abstract: Ipilimumab, the first immune-checkpoint inhibitor extending overall survival (OS) in metastatic melanoma patients, has a survival benefit only in a proportion of patients and the development of reliable predictive biomarkers is still an unmet need. To meet this request, we used a multivariate statistical approach to test whether myeloid-derived suppressor cells (MDSC) or other tumor-associated and immunological parameters may serve as predictive or prognostic biomarkers in melanoma patients receiving ipilimumab. By using a standardized approach to determine the circulating levels of four MDSC subsets, we observed a significant expansion of three MDSC subsets at baseline, as compared to controls and, upon treatment, that high levels of CD14+/IL4Rα+MDSCs were an independent prognostic factor of reduced OS. On the contrary, longer OS was associated to low levels of the proinflammatory proteins IL-6 and CRP and tumor-associated factors S100B and LDH both at baseline and after treatment. Increasing number of total T cells and especially of PD-1+/CD4+T cells were associated with better prognosis, and upregulation of PD-1+expression on CD4+T cells upon treatment was associated with lower toxicity. As several parameters were associated to OS, we included these factors in a multivariate survival model, and we identified IL-6 and ECOG PS as independent biomarkers associated with improved OS, whereas high levels of LDH and CD14+/IL4Rα+MDSCs were negative independent markers of reduced OS.
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Damuzzo
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Solito
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pinton
authors.affiliation: Department of Management and Engineering, University of Padova , Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Carrozzo
authors.affiliation: Istituto Oncologico Veneto IOV-IRCCS , Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Valpione
authors.affiliation: Istituto Oncologico Veneto IOV-IRCCS , Padova, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Pigozzo
authors.affiliation: Department of Civil, Environmental and Architectural Engineering, University of Padova , Padova, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Arboretti Giancristofaro
authors.affiliation: Istituto Oncologico Veneto IOV-IRCCS , Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Mandruzzato
keywords: Biomarkers; CTLA-4; ipilimumab; melanoma; myeloid-derived suppressor cells