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Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab
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Abstract
Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
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“Furthermore, an elevated eosinophil count prior to treatment was associated with longer overall survival in several studies.8–12”
In the citing paper
“increased lymphocyte counts in the blood are associated not only with favorable treatment outcome but also with increased overall survival in patients with melanoma treated with ICIs (132-135).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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“numerous studies of patients with cancer have indeed found that these myeloid cell subsets, whether in the tumor or in peripheral tissues, were negatively correlated with effective ICI therapy (134, 161, 168-171).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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“both a low baseline frequency of MDSCs and a low frequency of MDSCs in the blood of patients with melanoma following ipilimumab treatment were associated with favorable therapy outcome (134, 169-171).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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Does Baking Soda Function as a Magic Bullet for Patients With Cancer? A Mini Review
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Wen, S., Chen, N., Hu, Y., Huang, L., Peng, J., Yang, M., Shen, X., Song, Y., & Xu, L. (2021) · Cancer Medicine · doi:10.1002/cam4.3773 · Cited by 28
Role of myeloid-derived suppressor cells in tumor recurrence
Cole, K., Al-Kadhimi, Z. S., & Talmadge, J. E. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10079-1 · Cited by 30
“The CTLA-4 inhibitor ipilimumab, which was approved by the FDA for metastatic melanoma [289], has been shown to improve OS in patients with lower frequencies of MDSCs [290, 291].”
BackgroundGoldschmidt, J. H., Chou, L., Chan, P. K., Chen, L., Robert, N. J., Kinsey, J., Pitts, K., Nestor, M., Rock, E. P., & Lazarus, H. M. (2023) · Cancer Medicine · doi:10.1002/cam4.6645 · Cited by 27
“2 31 For example, increased blood absolute monocyte count (AMC) correlated with decreased overall survival for patients with melanoma receiving ICI therapy, 15,20,26 but not for those diagnosed with RCC. 17 Conversely, AMC correlated with variable survival in NSCLC across different studies.”
BackgroundPluvy, J., Brosseau, S., Naltet, C., Opsomer, M.-A., Cazes, A., Danel, C. J., Khalil, A., Zalcman, G., & Gounant, V. (2017) · European Respiratory Journal · doi:10.1183/13993003.00310-2017 · Cited by 27
Myeloid-derived suppressor cells and their role in gynecological malignancies
Mabuchi, S., Yokoi, E., Komura, N., & Kimura, T. (2018) · Tumor Biology · doi:10.1177/1010428318776485 · Cited by 29
Hude, I., Sasse, S., Bröckelmann, P. J., von Tresckow, B., Momotow, J., Engert, A., & Borchmann, S. (2018) · British Journal of Haematology · doi:10.1111/bjh.14705 · Cited by 27
Guo, Y., Wang, H., Liu, S., Zhang, X., Zhu, X., Huang, L., Zhong, W., Guan, L., Chen, Y., Xiao, M., et al. (2025) · Science Advances · doi:10.1126/sciadv.adp9009 · Cited by 27
“As melanoma tissue is rich in MDSCs ( 32 ), we treated fresh patient-derived melanoma tissue slices ( 33 ) with DR5-scFv sEVs.”
Current state and future of co-inhibitory immune checkpoints for the treatment of glioblastoma
Shen, S., Chen, L., Liu, J., Yang, L., Zhang, M., Wang, L., Zhang, R., Uemura, Y., Wu, Q., Yu, X., et al. (2020) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2020.0027 · Cited by 27
Baltussen, J. C., Welters, M. J. P., Verdegaal, E. M. E., Kapiteijn, E., Schrader, A. M. R., Slingerland, M., Liefers, G., van der Burg, S. H., Portielje, J. E. A., & de Glas, N. A. (2021) · Cancers · doi:10.3390/cancers13246366 · Cited by 28
“, Tregs) are more likely to respond to anti-CLTA-4 therapy [16].”
BackgroundResultZhang, Y., Liu, B., Kotenko, S. V., & Li, W. (2022) · Medicine · doi:10.1097/md.0000000000029536 · Cited by 31
“5 UNL OS Multivariate 6 Bisschop 2019([40]) Netherlands Pembrolizumab 147 2 UNL OS/PFS Multivariate 8 Chasset 2015([43]) France Ipilimumab 45 500 IU/ML OS Multivariate 7 Chasseuil 2018([30]) France Nivolumab 87 UNL OS Univariate 7 Damuzzo 2016([44]) Italy Ipilimumab 44 UNL OS Multivariate 7 Delyon 2013([45]) France Ip…”
Ostrand‐Rosenberg, S., Huecksteadt, T. P., & Sanders, K. A. (2023) · Cancers · doi:10.3390/cancers15041026 · Cited by 29
Halle, M. K., Sødal, M., Forsse, D., Engerud, H., Woie, K., Lura, N. G., Wagner-Larsen, K. S., Trovik, J., Bertelsen, B. I., Haldorsen, I. S., et al. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01305-0 · Cited by 27
Ezdoglian, A. A., Tsang-A-Sjoe, M. W. P., Khodadust, F., Burchell, G. L., Jansen, G., de Gruijl, T. D., Labots, M., & van der Laken, C. J. (2025) · Cancer and Metastasis Reviews · doi:10.1007/s10555-025-10246-6 · Cited by 27
“Sixty-nine percent of the studies had a moderate risk of bias, 13% – serious, and 9% – critical.”
InfluentialManipulation of Glucose Availability to Boost Cancer Immunotherapies
Marchesi, F., Vignali, D., Manini, B., Rigamonti, A., & Monti, P. (2020) · Cancers · doi:10.3390/cancers12102940 · Cited by 27
Addressing Resistance to Immune Checkpoint Inhibitor Therapy: An Urgent Unmet Need
Hu‐Lieskovan, S., Malouf, G. G., Jacobs, I. A., Chou, J., Liu, L., & Johnson, M. L. (2021) · Future Oncology · doi:10.2217/fon-2020-0967 · Cited by 26
Ipilimumab in a real‐world population: A prospective Phase IV trial with long‐term follow‐up
Aamdal, E., Jacobsen, K. D., Straume, O., Kersten, C., Herlofsen, O., Karlsen, J., Hussain, I., Amundsen, A., Dalhaug, A., Nyakas, M., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33768 · Cited by 26
“the ipilimumab registrational trial found survival benefit to be independent of LDH,(2) other reports have recognised an association between normal LDH and treatment efficacy.(14,16,17,20,22,30)”
BackgroundSalewski, I., Gladbach, Y. S., Kuntoff, S., Irmscher, N., Hahn, O., Junghanß, C., & Maletzki, C. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02570-y · Cited by 25
“Generally, the efficacy of cancer immunotherapy seems to be negatively correlated with MDSCs frequency and function [39, 40].”
BackgroundSalewski, I., Henne, J., Engster, L., Schneider, B., Lemcke, H., Skorska, A., Berlin, P., Henze, L., Junghanß, C., & Maletzki, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115990 · Cited by 25
Boudewijns, S., Koornstra, R. H. T., Westdorp, H., Schreibelt, G., van den Eertwegh, A. J. M., Foppen, M. H. G., Haanen, J. B. A. G., de Vries, I. J. M., Figdor, C. G., Bol, K. F., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1201625 · Cited by 25
“unlikely long-term benefit of ipilimumab treatment for patients with raised baseline serum LDH levels.(26,27)”
BackgroundSelf-citationBiomarkers in Malignant Melanoma: Recent Trends and Critical Perspective
Belter, B., Haase‐Kohn, C., & Pietzsch, J. (2017) · Codon Publications eBooks · doi:10.15586/codon.cutaneousmelanoma.2017.ch3 · Cited by 25
“An independent study showed that low baseline serum LDH is associated with favorable outcome of latestage melanoma patients treated with ipilimumab and, therefore, confirmed that baseline serum LDH is a strong marker for prognosis in advanced melanoma (11).”
BackgroundLang, B. M., Peveling‐Oberhag, A., Faidt, D., Hötker, A. M., Weyer‐Elberich, V., Grabbe, S., & Loquai, C. (2018) · Medical Oncology · doi:10.1007/s12032-018-1084-9 · Cited by 25
Combination immunotherapies implementing adoptive T-cell transfer for advanced-stage melanoma
Foley, K. C., Nishimura, M. I., & Moore, T. V. (2018) · Melanoma Research · doi:10.1097/cmr.0000000000000436 · Cited by 24
Regulation of T cell antitumor immune response by tumor induced metabolic stress
Chalmin, F., Bruchard, M., Végran, F., & Ghiringhelli, F. (2019) · Cell Stress · doi:10.15698/cst2019.01.171 · Cited by 23
“Recently it has been shown that tumor bed acidification blunts the efficacy of checkpoint inhibitors [80-82].”
BackgroundTasaki, Y., Hamamoto, S., Sugiyama, Y., Tomiyama, N., Naiki, T., Etani, T., Taguchi, K., Matsuyama, N., Sue, Y., Mimura, Y., et al. (2023) · International Journal of Urology · doi:10.1111/iju.15220 · Cited by 23
Lin, S. Y., Huang, S. K., Huynh, K. T., Salomon, M. P., Chang, S., Marzese, D. M., Lanman, R. B., Talasaz, A. H., & Hoon, D. S. �. (2018) · JCO Precision Oncology · doi:10.1200/po.17.00225 · Cited by 23
Gambichler, T., Brown, V., Steuke, A. ‐., Schmitz, L., Stockfleth, E., & Susok, L. (2017) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.14629 · Cited by 22
Predictive biomarkers for tumor immune checkpoint blockade
Tong, M., Wang, J., He, W., Wang, Y., Pan, H., Li, D., & Zhang, H. (2018) · Cancer Management and Research · doi:10.2147/cmar.s179680 · Cited by 22
Battaglia, A., Buzzonetti, A., Fossati, M., Scambia, G., Fattorossi, A., Madiyalakan, M. R., Mahnke, Y. D., & Nicodemus, C. F. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-019-02456-z · Cited by 21
Nair, N., Chen, S.-Y., Lemmens, E., Chang, S., Le, D. T., Jaffee, E. M., Murphy, A. L., Whiting, C. C., Müller, T., & Brockstedt, D. G. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0650 · Cited by 22
“Low baseline Lin CD14þHLA-DR–/low myeloid-derived suppressor cell (MDSC) and CD4þCD25þFoxP3þ Treg frequencies are associated with improved survival in the same indication and treatment context (23, 25).”
BackgroundBiomarkers for predicting the outcome of various cancer immunotherapies
Jafarzadeh, L., Khakpoor-Koosheh, M., Mirzaei, H., & Mirzaei, H. R. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103161 · Cited by 21
Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects
Pilla, L., Alberti, A., di Mauro, P., Gemelli, M. T., Cogliati, V., Cazzaniga, M. E., Bidoli, P., & Maccalli, C. (2020) · Cancers · doi:10.3390/cancers12113456 · Cited by 24
van der Sluis, T. C., Beyrend, G., van der Gracht, E. T. I., Abdelaal, T., Jochems, S. P., Belderbos, R. A., Wesselink, T. H., van Duikeren, S., van Haften, F. J., Redeker, A., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.100939 · Cited by 23
“Predictive biomarkers in patients treated with ICT, such PD-1 and CTLA-4 blockade, have also been investigated in the systemic circulation, showing key roles of T cells, natural killer (NK) cells,(34) and monocytes.(35,36) Here, we performed deep profiling of the systemic T cell response induced by immunotherapeutic r…”
BackgroundMyeloid-Derived Suppressor Cells (MDSC) in Melanoma Patients Treated with Anti-PD-1 Immunotherapy
Tomela, K., Pietrzak, B., Galus, Ł., Mackiewicz, J., SCHMIDT, M. T., Mackiewicz, A. A., & Kaczmarek, M. (2023) · Cells · doi:10.3390/cells12050789 · Cited by 23
“proposed a combined analysis of the baseline frequencies of MDSCs, Tregs, LDH and routine blood counts with clinical characteristics as a tool for predicting outcomes following ipilimumab therapy for advanced melanoma patients [32].”
BackgroundMethodResultInfluentialClinical evaluation of macrophages in cancer: role in treatment, modulation and challenges
Tremble, L. F., Forde, P. F., & Soden, D. M. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2065-0 · Cited by 22
Hurkmans, D. P., Verdegaal, E. M. E., Hogan, S. A., de Wijn, R., Hovestad, L., van den Heuvel, D. M. A., Ruijtenbeek, R., Welters, M. J. P., van Brakel, M., Basak, E. A., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001607 · Cited by 20
“In 18–28 Collectively, these studies indicate that the activation status and number of several immune cells in blood may provide minimally invasive predictive biomarkers that are suitable for routine clinical use.”
Eosinophils and melanoma: Implications for immunotherapy
Robinson, I., Lucia, G. S., Li, A. R., Oberholtzer, N. P., Plante, J. G., Quinn, K. M., Reuben, D. Y., Mehrotra, S., & Valdebran, M. (2021) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.13025 · Cited by 23
Wang, Y., Yang, S., Wan, L., Ling, W., Chen, H. H., & Wang, J. (2023) · International Journal of Oncology · doi:10.3892/ijo.2023.5534 · Cited by 22
Future perspectives in melanoma research “Melanoma Bridge”, Napoli, November 30th–3rd December 2016
Ascierto, P. A., Agarwala, S. S., Ciliberto, G., Demaria, S., Dummer, R., Duong, C. P. M., Ferrone, S., Formenti, S. C., Garbe, C., Halaban, R., et al. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-017-1341-2 · Cited by 23
“5%) had only a 3% response rate and median survival of 4 months [135].”
BackgroundSelf-citationCurrent knowledge of Ipilimumab and its use in treating non-small cell lung cancer
Pinto, J. A., Raez, L. E., Oliveres, H., & Rolfo, C. D. (2019) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2019.1610380 · Cited by 22
Bochem, J., Zelba, H., Amaral, T. M. S., Spreuer, J., Soffel, D., Eigentler, T., Wagner, N. B., Uslu, U., Terheyden, P. A. M., Meier, F. E., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221301 · Cited by 21
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Metadata
- Authors
- Martens, A., Wistuba-Hamprecht, K., Foppen, M. G., Yuan, J., Postow, M. A., Wong, P., Romano, E., Khammari, A., Dreno, B., Capone, M., Ascierto, P. A., Di Giacomo, A. M., Maio, M., Schilling, B., Sucker, A., Schadendorf, D., Hassel, J. C., Eigentler, T. K., Martus, P., Wolchok, J. D., Blank, C., Pawelec, G., Garbe, C., & Weide, B.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- 1Department of Dermatology, University Medical Center, Tübingen, Germany.
- The Netherlands Cancer Institute (NL)
- Memorial Sloan Kettering Cancer Center (US)
- Institut Curie (FR)
- Inserm (FR)
- 7Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- 9Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Italy.
- University of Siena (IT)
- Essen University Hospital (DE)
- Heidelberg University (DE)
- University of Tübingen (DE)
- Corresponding author
- Weide, Benjamin
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-06-14
- Volume
- 22
- Issue
- 12
- Pages
- 2908-2918
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5770142
- OpenAlex
- W2282962877
- Semantic Scholar
- 687f623ec6cd13653346165ccad52a8570919d07
- Cited by
- 541
- References
- 55
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 21 · 2023: 42 · 2022: 50 · 2021: 75 · 2020: 85 · 2019: 61 · 2018: 70 · 2017: 63 · 2016: 33
- FWCI
- 40.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Use Siena air (University of Siena) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Funders
- Bristol-Myers-Squibb (Munich, Germany) and EU Seventh Framework Program "PRIAT" (305309 and DFG PA 361-22/1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Keywords
- advanced melanoma, ipilimumab, predictive biomarkers, myeloid-derived suppressor cells, regulatory T cells, lactate dehydrogenase, absolute monocyte count, absolute eosinophil count, overall survival, best overall response, immune checkpoint inhibitors, anti-PD-1
- MeSH terms
- Myeloid-Derived Suppressor Cells, Antineoplastic Agents, Immunological, Ipilimumab, Aged, Erythrocyte Count, Female, Humans, L-Lactate Dehydrogenase, Male, Melanoma, Skin Neoplasms, Biomarkers, Tumor, Treatment Outcome, Lymphocyte Count, T-Lymphocytes, Regulatory
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