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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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BackgroundProgress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies
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Damuzzo, V., Solito, S., Pinton, L., Carrozzo, E., Valpione, S., Pigozzo, J., Arboretti, R., Chiarion‐Sileni, V., & Mandruzzato, S. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1249559 · Cited by 60
“describing the variations of the different MDSC subsets in response to ipilimumab.(18,19,23,24)”
BackgroundEmerging biomarkers for cancer immunotherapy in melanoma
Axelrod, M. L., Johnson, D. B., & Balko, J. M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.09.004 · Cited by 58
Almawash, S. (2025) · Cancers · doi:10.3390/cancers17050880 · Cited by 69
Cabel, L., Loir, E., Gravis, G., Lavaud, P., Massard, C., Albiges, L. K., Baciarello, G., Loriot, Y., & Fizazi, K. S. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0232-7 · Cited by 57
“In men with CRPC receiving ipilimumab, the number of blood PD-1 expressing CD4 T lymphocytes is associated with outcome [18, 19], although it is unknown whether this parameter is predictive of a treatment benefit.”
BackgroundNiwa, K., Kawakita, D., Nagao, T., Takahashi, H., Saotome, T., Okazaki, M., Yamazaki, K., Okamoto, I., Hirai, H., Saigusa, N., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73965-6 · Cited by 55
Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets
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“1%, while there were no survivors among 65 patients with higher MDSC levels [173].”
BackgroundButner, J. D., Elganainy, D., Wang, C. X., Wang, Z., Chen, S., Esnaola, N. F., Pasqualini, R., Arap, W., Hong, D. S., Welsh, J. W., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay6298 · Cited by 53
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Biomarkers for Response to Immune Checkpoint Blockade
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Eosinophils in the Tumor Microenvironment
Mattei, F., Andreone, S., Marone, G., Gambardella, A. R., Loffredo, S., Varricchi, G., & Schiavoni, G. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-49270-0_1 · Cited by 53
Meirow, Y., & Baniyash, M. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2035-6 · Cited by 54
“Others proposed that increased eosinophils and absolute lymphocyte count, along with low LDH, MDSCs, Tregs and related inflammatory factors as S100A8/A9 and HMGB1, can be used as novel, complex predictive markers for patients who may benefit from the ipilimumab therapy [20, 61].”
BackgroundWang, X., Zhang, B., Chen, X., Mo, H., Wu, D., Lan, B., Li, Q., Xu, B., & Huang, J. (2019) · Thoracic Cancer · doi:10.1111/1759-7714.13083 · Cited by 49
Immunotherapy-related biomarkers: Confirmations and uncertainties
Catalano, M., Iannone, L. F., Nesi, G., Nobili, S., Mini, E., & Roviello, G. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104135 · Cited by 61
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Eosinophils and Lung Cancer: From Bench to Bedside
Sibille, A., Corhay, J.-L., Louis, R. E., Ninane, V., Jérusalem, G., & Duysinx, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095066 · Cited by 48
Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer
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“Moreover, there is no consensus among the scientific community on highly specific markers to identify human MDSC.”
BackgroundInfluentialTuo, Z., Zheng, X., Zong, Y., Li, J., Zou, C., Lv, Y., & Liu, J. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.6 · Cited by 48
“Reportedly, high serum lactate dehydrogenase levels before and during treatment suggest that prognosis is not good.(13,14) The initial step of glycolysis operates in the presence of hexokinases (HKs).”
BackgroundSung, W., Grassberger, C., McNamara, A. L., Basler, L., Ehrbar, S., Tanadini‐Lang, S., Hong, T. S., & Paganetti, H. (2020) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2020.07.025 · Cited by 53
de Coaña, Y. P., Wolodarski, M., Àvila, I. V. D. H., Nakajima, T., Rentouli, S., Lundqvist, A., Masucci, G. V., Hansson, J., & Kiessling, R. W. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1786888 · Cited by 48
“LDH activity has already been described as a predictor of survival in melanoma and correlated with tumor burden, OS and responses to ipilimumab and pembrolizumab.(2,13,14) In the present study, LDH levels were correlated with overall survival, but were not found to be significantly higher in patients with short PFS ti…”
BackgroundMoore, T. V., Wagner, C. R., Scurti, G. M., Hutchens, K. A., Godellas, C. V., Clark, A. L., Kolawole, E. M., Hellman, L. M., Singh, N. K., Huyke‐Hernández, F. A., et al. (2017) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-017-2073-0 · Cited by 48
Emerging Biomarkers in Cutaneous Melanoma
Eisenstein, A. S., Gonzalez, E. C., Raghunathan, R., Xu, X., Wu, M., McLean, E. O., McGee, J. S., Ryu, B., & Alani, R. M. (2018) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-018-0318-z · Cited by 48
“Similarly, increased eosinophil count at baseline and through treatment with ipilimumab and pembrolizumab is associated with improved overall survival [204, 206, 210, 211].”
BackgroundCombination Immunotherapy Development in Melanoma
Eggermont, A. M. M., Crittenden, M. R., & Wargo, J. A. (2018) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_201131 · Cited by 47
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Considerations for successful cancer immunotherapy in aged hosts
Hurez, V. J., Padron, A. S., Svatek, R. S., & Curiel, T. J. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.10.002 · Cited by 46
“In 209 melanoma patients receiving αCTLA-4 immunotherapy, high Tregs (and also eosinophils and lymphocytes) correlated with better clinical outcomes (Martens et al., 2016a), but age was not specifically assessed as a variable.”
BackgroundInfluentialPrognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma
Nyakas, M., Aamdal, E., Jacobsen, K. D., Guren, T. K., Aamdal, S., Thorin‐Hagene, K., Brunsvig, P. F., Yndestad, A., Halvorsen, B. L., Taskén, K. A., et al. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13283 · Cited by 46
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Current status and future perspectives of immunotherapy in bladder cancer treatment
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“…have been associated with ipilimumab response in patients with melanoma, such as enhanced peripheral T cell levels, high absolute eosinophil counts, high peripheral FoxP3+ Treg numbers, and high CD4+/CD8+ lymphocyte counts (Martens et al., 2016; Simeone et al., 2014; van Dijk et al., 2019).”
BackgroundTumor resident regulatory T cells
Glasner, A., & Plitas, G. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101476 · Cited by 47
Queirolo, P., Dozin, B., Morabito, A., Banelli, B., Piccioli, P., Fava, C., Leo, C., Carosio, R., Laurent, S., Fontana, V., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00386 · Cited by 43
“Age, years, at first IPI cycle (median, range) 58.9 (26.6–88.2) Gender Male 96 (55.5) Female 77 (44.5) Primary melanoma subtype Cutaneous 130 (75.1) Mucosal 17 (9.8) Ocular 14 (8.1) Missing 12 (6.9) ECOG performance status 0 113 (65.3) 1 51 (29.5) 2 9 (5.2) Serum LDH Normal level 65 (37.6) ≥Upper limit of normal 92 (5…”
BackgroundInfluentialSelf-citationParikh, K., Kumar, A., Ahmed, J., Anwar, A., Puccio, C. A., Chun, H. G., Fanucchi, M. P., & Lim, S. H. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2192-2 · Cited by 44
“Unlike patients with advanced melanoma in whom low baseline AMCs predicted for improved median survival after therapy with ipilimumab [22], pre-treatment AMCs did not correlate with DoR in our patients with mNSCLC.”
BackgroundThe Immune Endocannabinoid System of the Tumor Microenvironment
Kienzl, M., Kargl, J., & Schicho, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238929 · Cited by 47
“It is, therefore, not surprising that increased frequencies of circulating MDSCs have been associated with poor disease prognosis in breast cancer melanoma patients [145].”
BackgroundRationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers
Tai, D. W.-M., Choo, S. P., & Chew, V. (2019) · Cancers · doi:10.3390/cancers11121926 · Cited by 43
“Treg Flow cytometry Melanoma High baseline frequency [89], on-therapy increased [95] or decreased [96] in frequency of circulating Treg was associated with disease control upon ICB.”
BackgroundDevelopment of Anti-Mouse CC Chemokine Receptor 3 Monoclonal Antibodies for Flow Cytometry
Asano, T., Nanamiya, R., Takei, J., Nakamura, T., Yanaka, M., Hosono, H., Tanaka, T., Sano, M., Kaneko, M. K., & Kato, Y. (2021) · Monoclonal Antibodies in Immunodiagnosis and Immunotherapy · doi:10.1089/mab.2021.0009 · Cited by 43
Blood Predictive Biomarkers for Nivolumab in Advanced Melanoma
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“In contrast, several studies found that higher Treg cell counts at baseline was associated with better prognosis in patients receiving anti-PD-(L)1 therapy (50, 51).”
ResultFerrucci, P. F., Gandini, S., Cocorocchio, E., Pala, L., Baldini, F., Mosconi, M., Cappellini, G. C. A., Albertazzi, E., & Martinoli, C. (2017) · Oncotarget · doi:10.18632/oncotarget.19748 · Cited by 41
“Associations of absolute baseline eosinophil counts with outcome of patients receiving ipilimumab have been documented [11].”
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Serum microRNA-based prediction of responsiveness to eribulin in metastatic breast cancer
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“In other studies, peripheral blood factors, such as low serum lactate dehydrogenase and relative lymphocyte count, were shown to be associated with better outcomes for patients with melanoma treated with pembrolizumab or ipilimumab, a PD-1 monoclonal antibody and a CTLA4 monoclonal antibody, respectively [20, 21].”
BackgroundTucker, M. D., Brown, L. C., Chen, Y., Kao, C., Hirshman, N. A., Kinsey, E. N., Ancell, K. K., Beckermann, K. E., Davis, N. B., McAlister, R. K., et al. (2021) · Biomarker Research · doi:10.1186/s40364-021-00334-4 · Cited by 43
Development of Anti-Mouse CC Chemokine Receptor 8 Monoclonal Antibodies for Flow Cytometry
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Svatoň, M., Zemanová, M., Skřičková, J., Jakubíková, L., Kolek, V., Kultan, J., Koubková, L., Bejčková, A., Salajka, F., Hrnčiarik, M., et al. (2018) · Anticancer Research · doi:10.21873/anticanres.13048 · Cited by 41
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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