Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

TY - JOUR

T1 - Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

AU - Gebhardt, Christoffer

AU - Sevko, Alexandra

AU - Jiang, Huanhuan

AU - Lichtenberger, Ramtin

AU - Reith, Maike

AU - Tarnanidis, Kathrin

AU - Holland-Letz, Tim

AU - Umansky, Ludmila

AU - Beckhove, Philipp

AU - Sucker, Antje

AU - Schadendorf, Dirk

AU - Utikal, Jochen

AU - Umansky, Viktor

N1 - ©2015 American Association for Cancer Research.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with metastatic melanoma. Because only around 20% of patients experience long-term benefit, reliable markers are needed to predict a clinical response. Therefore, we sought to determine if some myeloid cells and related inflammatory mediators could serve as predictive factors for the patients' response to ipilimumab.EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral blood of 59 stage IV melanoma patients before the treatment and at different time points upon the therapy using a clinical laboratory analysis and multicolor flow cytometry. In addition, the production of related inflammatory factors was evaluated by ELISA or Bio-Plex assays.RESULTS: An early increase in eosinophil count during the treatment with ipilimumab was associated with an improved clinical response. In contrast, elevated amounts of monocytic myeloid-derived suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders (n = 36) as compared with basal levels and with responding patients (n = 23). Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. ©2015 AACR.

AB - PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with metastatic melanoma. Because only around 20% of patients experience long-term benefit, reliable markers are needed to predict a clinical response. Therefore, we sought to determine if some myeloid cells and related inflammatory mediators could serve as predictive factors for the patients' response to ipilimumab.EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral blood of 59 stage IV melanoma patients before the treatment and at different time points upon the therapy using a clinical laboratory analysis and multicolor flow cytometry. In addition, the production of related inflammatory factors was evaluated by ELISA or Bio-Plex assays.RESULTS: An early increase in eosinophil count during the treatment with ipilimumab was associated with an improved clinical response. In contrast, elevated amounts of monocytic myeloid-derived suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders (n = 36) as compared with basal levels and with responding patients (n = 23). Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. ©2015 AACR.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal

KW - Antineoplastic Agents

KW - Biomarkers

KW - Combined Modality Therapy

KW - Female

KW - Humans

KW - Immunophenotyping

KW - Inflammation Mediators

KW - Ipilimumab

KW - Leukocyte Count

KW - Male

KW - Melanoma

KW - Middle Aged

KW - Myeloid Cells

KW - Neoplasm Staging

KW - Phenotype

KW - Prognosis

KW - Retrospective Studies

KW - Treatment Outcome

KW - Journal Article

KW - Multicenter Study

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/1078-0432.CCR-15-0676

DO - 10.1158/1078-0432.CCR-15-0676

M3 - SCORING: Journal article

C2 - 26289067

VL - 21

SP - 5453

EP - 5459

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 24

ER -