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


METHODS
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.
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. v.umansky@dkfz.de c.gebhardt@dkfz.de.
Christoffer
C
Gebhardt
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
Alexandra
A
Sevko
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The First Hospital Affiliated to Anhui Medical University, Hefei, China.
Huanhuan
H
Jiang
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
Ramtin
R
Lichtenberger
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
Maike
M
Reith
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
Kathrin
K
Tarnanidis
Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Tim
T
Holland-Letz
Department of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ludmila
L
Umansky
Department of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Philipp
P
Beckhove
Department of Dermatology, University Hospital Essen, Essen, Germany & German Cancer Consortium, Heidelberg, Germany.
Antje
A
Sucker
Department of Dermatology, University Hospital Essen, Essen, Germany & German Cancer Consortium, Heidelberg, Germany.
Dirk
D
Schadendorf
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany.
Jochen
J
Utikal
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. v.umansky@dkfz.de c.gebhardt@dkfz.de.
Viktor
V
Umansky
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism*; D000074324:Ipilimumab; D007958:Leukocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D000074324:Ipilimumab