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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An elevated eosinophil count prior to treatment was associated with longer overall survival in several studies.
“Furthermore, an elevated eosinophil count prior to treatment was associated with longer overall survival in several studies.8–12”
Increased lymphocyte counts in the blood are associated with favorable treatment outcome and increased overall survival in melanoma patients treated with immune checkpoint inhibitors.
“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]
In cancer patients, myeloid cell subsets (macrophages, MDSCs) in tumor or peripheral tissues are negatively correlated with effective immune checkpoint inhibitor therapy.
“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]
Low baseline frequency of MDSCs and low frequency of MDSCs in blood of melanoma patients following ipilimumab treatment were associated with favorable therapy outcome.
“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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“11–13, 23, 24), the neutrophil count (25), or the neutrophil to lymphocyte ratio (26)was reported by different groups as other possible biomarkers.”
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“An association of high AMC with poor prognosis was reported before (37, 38), but baseline counts were not predictive for ipilimumab-treated patients in the study of Kitano and colleagues (10).”
BackgroundSchindler, K., Harmankaya, K., Postow, M. A., Frantal, S., Bello, D., Ariyan, C. E., Michielin, O. A., Hoeller, C., Pehamberger, H., & Wolchok, J. D. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.9024 · Cited by 30 · cited 1× · see citing works
“Similar findings were reported by Schindler and colleagues at the ASCOmeeting 2013 (36) and an increase of eosinophils during ipilimumab was associated with OS in the study of Delyon and colleagues (12).”
ResultSelf-citationHarrell, F., Jr. (1996) · doi:10.1002/(sici)1097-0258(19960229)15:4
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The immune contexture in cancer prognosis and treatment
Fridman, W. H., Zitvogel, L., Sautès–Fridman, C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.101 · Cited by 2,263 · see citing works
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Immune checkpoint inhibitors: recent progress and potential biomarkers
Darvin, P., Toor, S. M., Sasidharan Nair, V., & Elkord, E. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0191-1 · Cited by 2,035 · see citing works
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
Havel, J. J., Chowell, D., & Chan, T. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0116-x · Cited by 2,286 · see citing works
Myeloid-derived suppressor cells coming of age
Veglia, F., Perego, M., & Gabrilovich, D. I. (2018) · Nature Immunology · doi:10.1038/s41590-017-0022-x · Cited by 1,774 · see citing works
Predictive biomarkers for checkpoint inhibitor-based immunotherapy
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“Hence, MDSCs have been reported to be potential predictors of resistance to the anti-CTLA-4 mAb ipilimumab in patients with prostate cancer or melanoma (Martens et al., 2016; Meyer et al., 2014; Santegoets et al., 2014).”
Monitoring immune-checkpoint blockade: response evaluation and biomarker development
Nishino, M., Ramaiya, N. H., Hatabu, H., & Hodi, F. S. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.88 · Cited by 1,023 · see citing works
Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab
Weide, B., Martens, A., Hassel, J. C., Berking, C., Postow, M. A., Bisschop, K., Simeone, E., Mangana, J., Schilling, B., Di Giacomo, A. M., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0127 · Cited by 589 · see citing works
“For ipilimumab, high REC at baseline was correlated with favorable OS (25, 39) and early increases during treatment was associated with improved clinical responses (40).”
BackgroundSelf-citationHeinhuis, K. M., Ros, W., Kok, M., Steeghs, N., Beijnen, J. H., & Schellens, J. H. M. (2019) · Annals of Oncology · doi:10.1093/annonc/mdy551 · Cited by 556 · see citing works
“[10] Low leukocyte count at baseline correlates with response Melanoma Ipilimumab Gebhardt et al.”
BackgroundMyeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors
Weber, R., Fleming, V., Hu, X., Nagibin, V. S., Groth, C., Altevogt, P., Utikal, J. S., & Umansky, V. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01310 · Cited by 535 · see citing works
“It was shown by three more studies that a lower frequency of circulating MDSC at baseline can be used as a predictive marker for ipilimumab treatment of malignant melanoma patients (14, 15, 63).”
BackgroundChaudhary, B., & Elkord, E. (2016) · Vaccines · doi:10.3390/vaccines4030028 · Cited by 516 · see citing works
Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors
Bai, R., Lv, Z., Xu, D., & Cui, J. (2020) · Biomarker Research · doi:10.1186/s40364-020-00209-0 · Cited by 469 · see citing works
“Low baseline lactate dehydrogenase (LDH) levels, high relative/absolute eosinophil counts, and relative lymphocyte counts were associated with prolonged OS in anti-PD-1 and CTLA-4 treated melanoma [97, 98].”
BackgroundThe Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression
Umansky, V., Blattner, C., Gebhardt, C., & Utikal, J. S. (2016) · Vaccines · doi:10.3390/vaccines4040036 · Cited by 440 · see citing works
Rotte, A., Jin, J., & Lemaire, V. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx686 · Cited by 346 · see citing works
Biomarkers of response to PD-1/PD-L1 inhibition
Vareki, S. M., Garrigós, C., & Durán, I. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.06.001 · Cited by 319 · see citing works
IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy
Weber, R., Groth, C., Lasser, S., Arkhypov, I., Petrova, V., Altevogt, P., Utikal, J. S., & Umansky, V. (2020) · Cellular Immunology · doi:10.1016/j.cellimm.2020.104254 · Cited by 310 · see citing works
A new dawn for eosinophils in the tumour microenvironment
Grisaru‐Tal, S., Itan, M., Klion, A. D., & Munitz, A. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0283-9 · Cited by 305 · see citing works
Eosinophils: The unsung heroes in cancer?
Varricchi, G., Galdiero, M. R., Loffredo, S., Lucarini, V., Marone, G., Mattei, F., Marone, G., & Schiavoni, G. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1393134 · Cited by 280 · see citing works
Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy
Galli, F., Aguilera, J. V., Palermo, B., Markovic, S. N., Nisticò, P., & Signore, A. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01586-y · Cited by 280 · see citing works
“N2 TANs through the secretion of MMPs and interleukin (IL)-1β activates endothelial cells and inhibits NK cells, promoting tumor cell plasticity [56] and cancer migration [57].”
BackgroundMDSC; the Most Important Cell You Have Never Heard Of
Tesi, R. J. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.10.008 · Cited by 265 · see citing works
Oliva, M., Spreafico, A., Taberna, M., Alemany, L., Coburn, B. A., Mesı́a, R., & Siu, L. L. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy507 · Cited by 261 · see citing works
“In this regard, the predictive value of response to ICIs offered by immunophenotyping of circulating T-cell subsets versus TILs has demonstrated relevance in melanoma and NSCLC but it is still unknown in HNSCC [100, 101].”
BackgroundParihar, R., Rivas, C. H., Huynh, M., Omer, B. A., Lapteva, N., Metelitsa, L. S., Gottschalk, S. M., & Rooney, C. M. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0572 · Cited by 254 · see citing works
“Given that high baseline numbers of MDSCs have been reported as a biomarker of poor response in the context of trials with the checkpoint inhibitors ipilimumab and pembrolizumab (35, 36), elimination of MDSCs by NKG2D.”
BackgroundDiehl, A., Yarchoan, M. M., Hopkins, A., Jaffee, E. M., & Grossman, S. A. (2017) · Oncotarget · doi:10.18632/oncotarget.23217 · Cited by 247 · see citing works
Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment
Arrieta, V. A., Dmello, C., McGrail, D. J., Brat, D. J., Lee-Chang, C., Heimberger, A. B., Chand, D. S., Stupp, R., & Sonabend, A. M. (2023) · Journal of Clinical Investigation · doi:10.1172/jci163447 · Cited by 244 · see citing works
Exploiting innate immunity for cancer immunotherapy
Yi, M., Li, T., Niu, M., Mei, Q., Zhao, B., Chu, Q., Dai, Z., & Wu, K. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01885-w · Cited by 236 · see citing works
Tanizaki, J., Haratani, K., Hayashi, H., Chiba, Y., Nakamura, Y., Yonesaka, K., Kudo, K., Kaneda, H., Hasegawa, Y., Tanaka, K., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.10.030 · Cited by 223 · see citing works
Buder‐Bakhaya, K., & Hassel, J. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01474 · Cited by 214 · see citing works
“A high pre-ICI absolute or relative eosinophil count was associated with prolonged OS (23, 41).”
BackgroundInfluentialSelf-citationMyeloid-Derived Suppressor Cells in the Tumor Microenvironment
Dysthe, M., & Parihar, R. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-35723-8_8 · Cited by 210 · see citing works
Lactate dehydrogenase: a marker of diminished antitumor immunity
Wilpe, S. V., Koornstra, R. H. T., den Brok, M. H., de Groot, J. W., Blank, C. U., de Vries, I. J. M., Gerritsen, W. R., & Mehra, N. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1731942 · Cited by 210 · see citing works
Self-citationCancer immunotherapy: it’s time to better predict patients’ response
Pilard, C., Ancion, M., Delvenne, P., Jérusalem, G., Hubert, P., & Herfs, M. F. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01413-x · Cited by 214 · see citing works
Valpione, S., Pasquali, S., Campana, L. G., Piccin, L., Mocellin, S., Pigozzo, J., & Chiarion-Sileni, V. (2018) · Journal of Translational Medicine · doi:10.1186/s12967-018-1467-x · Cited by 201 · see citing works
“As consequence, although the role of the biomarkers that we investigated is unknown in contexts of combination immunotherapy and anti-PD1 drugs, the present study could have a clinical relevance in a large patient population and, to our knowledge, is one of the first planned to look for predictors of immune-toxicity […”
BackgroundMasucci, G. V., Cesano, A., Hawtin, R. E., Janetzki, S., Zhang, J., Kirsch, I. R., Dobbin, K. K., Alvarez, J. D., Robbins, P. B., Selvan, S. R., et al. (2016) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-016-0178-1 · Cited by 200 · see citing works
“Interestingly, higher baseline frequencies of circulating CD4 + CD25 + FoxP3+ Tregs were associated with improved overall survival (OS) in this patient population [20].”
BackgroundInfluentialLimagne, E., Richard, C., Thibaudin, M., Fumet, J.-D., Truntzer, C., Lagrange, A., Favier, L., Coudert, B. P., & Ghiringhelli, F. (2019) · OncoImmunology · doi:10.1080/2162402x.2018.1564505 · Cited by 200 · see citing works
The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?
Franzin, R., Netti, G. S., Spadaccino, F., Porta, C., Gesualdo, L., Stallone, G., Castellano, G., & Ranieri, E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.574271 · Cited by 203 · see citing works
“Systemic biomarkers of irAEs as lymphocytes and eosinophils counts, neutrophil-to-lymphocytes ratio (123, 124), and cytokine circulating level have been assessed due to poor invasive and routine measurements.”
BackgroundLucarini, V., Ziccheddu, G., Macchia, I., Sorsa, V. L., Peschiaroli, F., Buccione, C., Sistigu, A., Sanchez, M., Andreone, S., D’Urso, M. T., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1317420 · Cited by 199 · see citing works
Heppt, M. V., Heinzerling, L., Kähler, K. C., Forschner, A., Kirchberger, M. C., Loquai, C., Meißner, M., Meier, F. E., Terheyden, P. A. M., Schell, B., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.05.038 · Cited by 199 · see citing works
Self-citationPredictors of responses to immune checkpoint blockade in advanced melanoma
Jacquelot, N., Roberti, M. P., Enot, D. P., Rusakiewicz, S., Ternès, N., Jegou, S., Woods, D. M., Sodré, A. L., Hansen, M., Meirow, Y., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00608-2 · Cited by 196 · see citing works
Self-citationExisting and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors
Arora, S., Velichinskii, R. A., Lesh, R. W., Ali, U., Kubiak, M. J., Bansal, P., Borghaei, H., Edelman, M. J., & Boumber, Y. (2019) · Advances in Therapy · doi:10.1007/s12325-019-01051-z · Cited by 197 · see citing works
Regulatory cells and the effect of cancer immunotherapy
Iglesias-Escudero, M., Arias-González, N., & Martínez-Cáceres, E. M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01714-0 · Cited by 195 · see citing works
“For instance, in a study aimed at identifying biomarkers associated with clinical outcome in melanoma patients, the decrease in FOXP3 + /regulatory T cells (Tregs) was associated with better clinical responses in the group treated with ipilimumab [5].”
BackgroundPredictive biomarkers of response for immune checkpoint inhibitors in non–small-cell lung cancer
Prelaj, A., Tay, R. Y., Ferrara, R., Chaput, N., Besse, B., & Califano, R. (2018) · European Journal of Cancer · doi:10.1016/j.ejca.2018.11.002 · Cited by 193 · see citing works
Subrahmanyam, P. B., Dong, Z., Gusenleitner, D., Giobbie-Hurder, A., Severgnini, M., Zhou, J., Manos, M., Eastman, L. M., Maecker, H. T., & Hodi, F. S. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0328-8 · Cited by 190 · see citing works
“showed that low absolute monocyte count and high relative lymphocyte count were significantly associated with better survival in anti-CTLA-4 treated melanoma patients [18].”
BackgroundResultImmune checkpoint inhibitors: a promising anticancer therapy
Singh, S., Hassan, D., Aldawsari, H. M., Molugulu, N., Shukla, R., & Kesharwani, P. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.11.003 · Cited by 191 · see citing works
Dominguez, G. A., Condamine, T., Mony, S., Hashimoto, A., Wang, F., Liu, Q., Forero, A., Bendell, J., Witt, R., Hockstein, N., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1784 · Cited by 187 · see citing works
“Clin Cancer Res; 23(12) June 15, 2017 Clinical Cancer Research 2948”
BackgroundInfluentialTargeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
Tengesdal, I. W., Menon, D. R., Osborne, D. G., Neff, C., Powers, N. E., Gamboni, F., Mauro, A., D'Alessandro, A., Stefanoni, D., Henen, M., et al. (2021) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2000915118 · Cited by 166 · see citing works
Biochemistry, Lactate Dehydrogenase
Farhana, A., & Lappin, S. L. (2021) · StatPearls · Cited by 185 · see citing works
Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events
Nakamura, Y. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00119 · Cited by 184 · see citing works
“demonstrated that in melanoma patients treated with ipilimumab, high absolute, and relative eosinophil counts at baseline were associated with a longer OS (38).”
BackgroundInfluentialMartens, A., Wistuba-Hamprecht, K., Yuan, J., Postow, M. A., Wong, P., Capone, M., Madonna, G., Khammari, A., Schilling, B., Sucker, A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0249 · Cited by 180 · see citing works
“This is especially true for MDSCs that were proposed as baseline biomarkers for ipilimumab treatment outcome earlier (9, 26).”
BackgroundMethodResultInfluentialSelf-citationHopkins, A. M., Rowland, A., Kichenadasse, G., Wiese, M. D., Gurney, H., McKinnon, R. A., Karapetis, C. S., & Sorich, M. J. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.274 · Cited by 178 · see citing works
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Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic
Grover, A., Sanseviero, E., Timosenko, E., & Gabrilovich, D. I. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0764 · Cited by 176 · see citing works
Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer
Wang, L., Simons, D. L., Lu, X., Tu, T. Y., Solomon, S. T., Wang, R., Rosario, A., Avalos, C., Schmolze, D. B., Yim, J. H., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0429-7 · Cited by 174 · see citing works
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Biomarkers associated with checkpoint inhibitors
Manson, G., Norwood, J., Marabelle, A., Kohrt, H. E. K., & Houot, R. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw181 · Cited by 164 · see citing works
Myeloid cell heterogeneity in cancer: not a single cell alike
Kiss, M., Van Gassen, S., Movahedi, K., Saeys, Y., & Laoui, D. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.02.008 · Cited by 159 · see citing works
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Hogan, S. A., Courtier, A., Cheng, P. F., Jaberg-Bentele, N. F., Goldinger, S. M., Manuel, M., Perez, S., Plantier, N., Mouret, J.-F., Nguyen‐Kim, T. D. L., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0136 · Cited by 153 · see citing works
Kluger, H. M., Zito, C. R., Turcu, G., Baine, M. K., Zhang, H., Adeniran, A., Sznol, M., Rimm, D. L., Kluger, Y., Chen, L., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3146 · Cited by 151 · see citing works
“To date, despite a number of attempts to identify biomarkers predictive of response to ipilimumabmonotherapy, no biomarker has consistently been shown to be associated with response or clinical benefit (15, 16).”
BackgroundPlitas, G., & Rudensky, A. Y. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033428 · Cited by 148 · see citing works
“Higher pretreatment levels of circulating Treg cells were associated with improved survival in melanoma patients treated with ipilimumab (Martens et al. 2016).”
BackgroundHou, A., Hou, K., Huang, Q., Lei, Y., & Chen, W.-L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00783 · Cited by 147 · see citing works
de Coaña, Y. P., Wolodarski, M., Poschke, I., Yoshimoto, Y., Yang, Y., Nyström, M., Edbäck, U., Brage, S. E., Lundqvist, A., Masucci, G. V., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15368 · Cited by 139 · see citing works
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Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
Gray, J. E., Saltos, A. N., Tanvetyanon, T., Haura, E. B., Creelan, B., Antonia, S. J., Shafique, M. R., Zheng, H., Dai, W., Saller, J. J., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1305 · Cited by 143 · see citing works
Kim, S. H., Li, M., Trousil, S., Zhang, Y., di Magliano, M. P., Swanson, K. D., & Zheng, B. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.03.033 · Cited by 140 · see citing works
“Indeed, MDSCs have been proposed to contribute to resistance to various cancer therapies, including to anti-CTLA4 and anti-PD-1 blockade (Martens et al., 2016; Sade-Feldman et al., 2016; Weber et al., 2016).”
BackgroundPawelec, G. (2017) · Biogerontology · doi:10.1007/s10522-017-9682-z · Cited by 140 · see citing works
“…anecdotal clinical reports with sufficient accumulated experience, at least for the treatment of advanced melanoma with anti-CTLA-4 antibodies, it seems that response rates may be quite similar in elderly and younger patients (Martens et al. 2016; Helissey et al. 2016; Chiarion Sileni et al. 2014).”
BackgroundSelf-citationBiomarkers for Immunotherapy: Current Developments and Challenges
Spencer, K. R., Wang, J., Silk, A. W., Ganesan, S., Kaufman, H. L., & Mehnert, J. M. (2016) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_160766 · Cited by 147 · see citing works
Heppt, M. V., Amaral, T. M. S., Kähler, K. C., Heinzerling, L., Hassel, J. C., Meißner, M., Kreuzberg, N., Loquai, C., Reinhardt, L., Utikal, J. S., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0800-0 · Cited by 141 · see citing works
“As potential serum biomarkers, lactate dehydrogenase (LDH), C-reactive protein (CRP), and the relative counts of lymphocytes (RLC), neutrophils (RNC), and eosinophils (REC) were specifically collected from patient charts and analyzed for their prognostic value [13, 14].”
BackgroundSelf-citationPrognostic role of neutrophil‐to‐lymphocyte ratio in head and neck cancer: A meta‐analysis
Takenaka, Y., Oya, R., Kitamiura, T., Ashida, N., Shimizu, K., Takemura, K., Yamamoto, Y., & Uno, A. (2017) · Head & Neck · doi:10.1002/hed.24986 · Cited by 137 · see citing works
Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy
Makuku, R., Khalili, N., Razi, S., Keshavarz-Fathi, M., & Rezaei, N. (2021) · Journal of Immunology Research · doi:10.1155/2021/6661406 · Cited by 136 · see citing works
“lymphocyte count (ALC), absolute neutrophil count (ANC), and absolute eosinophil count (AEC), were related to survival in melanoma patients undergoing treatment with immune checkpoint inhibitor therapy [115, 116].”
BackgroundWang, P.-F., Song, S., Wang, T., Ji, W., Li, S., Liu, N., & Yan, C. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1494113 · Cited by 133 · see citing works
Systemic Reprogramming of Monocytes in Cancer
Kiss, M., Caro, A. A., Raes, G., & Laoui, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01399 · Cited by 132 · see citing works
“Recent studies have revealed that phenotypical alterations in peripheral blood monocytes can serve as diagnostic (113, 117), predictive (108), and prognostic (116) biomarkers.”
BackgroundEosinophil–lymphocyte interactions in the tumor microenvironment and cancer immunotherapy
Grisaru‐Tal, S., Rothenberg, M. E., & Munitz, A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01291-2 · Cited by 131 · see citing works
Nosrati, A., Tsai, K. K., Goldinger, S. M., Tumeh, P. C., Grimes, B. A., Loo, K. L., Algazi, A. P., Nguyen‐Kim, T. D. L., Levesque, M. P., Dummer, R., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.70 · Cited by 125 · see citing works
“…cell populations, such as MDSCs and Treg cells (Pawelec et al, 2010; Goronzy and Weyand, 2013), and MDSCs have been reported as potential predictors of resistance to ipilimumab therapy (Meyer et al, 2014; Martens et al, 2016), which would suggest a similar effect in anti-PD-1-treated patients.”
BackgroundHarnessing the chemokine system to home CAR-T cells into solid tumors
Foeng, J., Comerford, I., & McColl, S. R. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100543 · Cited by 127 · see citing works
“An analysis of 209 advanced melanoma patients identified multiple parameters that correlate with prolonged survival following ipilimumab (a-CTLA-4) treatment, including low baseline serum lactate dehydrogenase levels and monocyte, eosinophil, and lymphocyte abundance.(75) Furthermore, CyTOF analysis of peripheral bloo…”
BackgroundThe Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer
van Dijk, N., Funt, S. A., Blank, C. U., Powles, T. B., Rosenberg, J. E., & van der Heijden, M. S. (2018) · European Urology · doi:10.1016/j.eururo.2018.09.022 · Cited by 121 · see citing works
Self-citationRosner, S., Kwong, E., Shoushtari, A. N., Friedman, C. F., Warner, A. B., Brady, M. S., Coit, D. G., Callahan, M. K., Wolchok, J. D., Chapman, P. B., et al. (2018) · Cancer Medicine · doi:10.1002/cam4.1356 · Cited by 124 · see citing works
“Nonetheless, our finding that monocytes were negatively associated with outcomes is consistent with other studies [12, 25].”
BackgroundResultSelf-citationTengesdal, I. W., Dinarello, A., Powers, N. E., Burchill, M. A., Joosten, L. A. B., Marchetti, C., & Dinarello, C. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661323 · Cited by 121 · see citing works
“Levels of MDSCs have been proposed as a predictive marker for response to immunotherapy (43, 44).”
BackgroundMastio, J., Condamine, T., Dominguez, G., Kossenkov, A. V., Donthireddy, L., Veglia, F., Lin, C., Wang, F., Fu, S., Zhou, J., et al. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20181952 · Cited by 115 · see citing works
“, 2016; Wang and Yang, 2016), including immunotherapies (Kimura et al., 2013; Martens et al., 2016; Sade-Feldman et al., 2016; Weber et al., 2016; Butterfield et al., 2017; de Coaña et al., 2017).”
Barta, S. K., Zain, J. M., Macfarlane, A. W., Smith, S. M., Ruan, J., Fung, H. C. H., Tan, C. R. C., Yang, Y., Alpaugh, R. K., Dulaimi, E., et al. (2019) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2019.03.022 · Cited by 119 · see citing works
Alicea-Torres, K. M., Sanseviero, E., Gui, J., Chen, J., Veglia, F., Yu, Q., Donthireddy, L., Kossenkov, A. V., Lin, C., Fu, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22033-2 · Cited by 120 · see citing works
The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy
Wang, X., Wang, F., Zhong, M., Yarden, Y., & Fu, L. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01200-x · Cited by 120 · see citing works
Predictive biomarkers for response to immune checkpoint inhibition
Shum, B., Larkin, J., & Turajlic, S. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.036 · Cited by 117 · see citing works
Targeting inflammation as cancer therapy
Wang, M., Chen, S., He, X., Yuan, Y., & Wei, X. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01528-7 · Cited by 122 · see citing works
“For instance, patients with lower fractions of circulating MDSCs are more sensitive to ipili-mumab treatment [89], especially melanoma patients [90, 91].”
BackgroundChesney, J. A., Mitchell, R. A., & Yaddanapudi, K. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5vmr1116-458rrr · Cited by 117 · see citing works
Wistuba-Hamprecht, K., Martens, A., Heubach, F., Romano, E., Geukes Foppen, M., Yuan, J., Postow, M., Wong, P., Mallardo, D., Schilling, B., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2016.12.011 · Cited by 108 · see citing works
“The prognostic impact of frequencies of other circulating immune cell subsets such as myeloidderived suppressor cells, Tregs and gd T-cells was reported by us before in partially overlapping cohorts [31,43,44].”
Self-citationMonitoring immune responses in the tumor microenvironment
Wargo, J. A., Reddy, S. M., Reuben, A., & Sharma, P. (2016) · Current Opinion in Immunology · doi:10.1016/j.coi.2016.05.006 · Cited by 113 · see citing works
“Though prognostic signatures to therapy have been described [11,26,27], phenotypic analysis of conventional markers in peripheral blood alone does not provide sufficient information about the tumor immune microenvironment and should be discouraged.”
MethodZhang, W., Yan, C., Zhang, T., Chen, X., Dong, J., Zhao, J., Han, D., Wang, J., Zhao, G., Cao, F., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1971418 · Cited by 111 · see citing works
PD-1 and LAG-3 Dominate Checkpoint Receptor–Mediated T-cell Inhibition in Renal Cell Carcinoma
Zelba, H., Bedke, J., Hennenlotter, J., Mostböck, S., Zettl, M., Zichner, T., Chandran, A., Stenzl, A., Rammensee, H., & Gouttefangeas, C. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0146 · Cited by 105 · see citing works
“Baseline levels of LDH are associated with survival upon checkpoint blockade therapy (26).”
BackgroundKomura, N., Mabuchi, S., Shimura, K., Yokoi, E., Kozasa, K., Kuroda, H., Takahashi, R., Sasano, T., Kawano, M., Matsumoto, Y., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02628-2 · Cited by 105 · see citing works
“It was recently reported that higher MDSC numbers are associated with a poorer clinical outcome following treatment with checkpoint inhibitors [36, 37], the reason and solution for which remain unknown.”
BackgroundThe role of cancer stem cells in the modulation of anti-tumor immune responses
Maccalli, C., Rasul, K. I., Elawad, M., & Ferrone, S. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.09.006 · Cited by 104 · see citing works
“Of note, the presence of MDSCs in TME can be associated with patients’ survival [141], and these cells have been shown also to be a predictive marker of clinical activity of immunotherapy in melanoma patients [151,152].”
BackgroundUgurel, S., Schadendorf, D., Horny, K., Sucker, A., Schramm, S., Utikal, J. S., Pföhler, C., Herbst, R. A., Schilling, B., Blank, C. U., et al. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2019.09.005 · Cited by 106 · see citing works
Self-citationPeripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors
An, H. J., Chon, H. J., & Kim, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179414 · Cited by 105 · see citing works
“However, regarding Tregs, the results are controversial; while some studies revealed a positive correlation, another study reported a negative correlation, and other studies reported no such relationship between Tregs and ICI outcomes [27,30,36,41,43,45].”
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Metabolic flexibility in melanoma: A potential therapeutic target
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Agrawal, L., Engel, K. B., Greytak, S. R., & Moore, H. M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.12.008 · Cited by 99 · see citing works
“A higher frequency of myeloid-derived suppressor cells (MDSCs) and CD4+, CD25+, FoxP3+ regulatory T-cells (or Tregs) were associated with an improvement in overall patient survival among melanoma patients receiving Ipilimumab [147].”
Fujisawa, Y., Yoshino, K., Otsuka, A., Funakoshi, T., Fujimura, T., Yamamoto, Y., Hata, H., Gosho, M., Tanaka, R., Yamaguchi, K., et al. (2017) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2017.07.007 · Cited by 101 · see citing works
Liquid biomarkers in melanoma: detection and discovery
Lim, S. Y., Lee, J., Diefenbach, R. J., Kefford, R. F., & Rizos, H. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0757-5 · Cited by 95 · see citing works
“In a study with 209 melanoma patients treated with ipilimumab, low absolute monocyte counts, and high absolute eosinophil count, T regulatory cells and relative lymphocyte counts were associated with a favorable outcome [128].”
BackgroundDoes patient age influence anti-cancer immunity?
Pawelec, G. (2018) · Seminars in Immunopathology · doi:10.1007/s00281-018-0697-6 · Cited by 96 · see citing works
Self-citation
- 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 · 2014: 1
- 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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