Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

Sade-Feldman, Moshe; Kanterman, Julia; Klieger, Yair; Ish-Shalom, Eliran; Mizrahi, Olga; Saragovi, Amijai; Shtainberg, Hani; Lotem, Michal; Baniyash, Michal

doi:10.1158/1078-0432.ccr-15-3104

Cited by 173 publications

(138 citation statements)

References 43 publications

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“…Indeed, the role of MDSCs as a biomarker for ipilimumab treatment was demonstrated in a number of studies, mostly reporting correlations between monocytic MDSCs and clinical response. 18,23,24,[29][30][31][32] Kitano and colleagues developed a computational algorithm-based method to perform a uniform analysis of the levels of a monocytic subset in melanoma patients treated with ipilimumab at 3 or 10 mg/kg and found a significant association between levels of Lin…”

Section: Discussionmentioning

confidence: 99%

Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab

et al. 2016

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Ipilimumab, the first immune-checkpoint inhibitor extending overall survival (OS) in metastatic melanoma patients, has a survival benefit only in a proportion of patients and the development of reliable predictive biomarkers is still an unmet need. To meet this request, we used a multivariate statistical approach to test whether myeloid-derived suppressor cells (MDSC) or other tumor-associated and immunological parameters may serve as predictive or prognostic biomarkers in melanoma patients receiving ipilimumab. By using a standardized approach to determine the circulating levels of four MDSC subsets, we observed a significant expansion of three MDSC subsets at baseline, as compared to controls and, upon treatment, that high levels of CD14 C /IL4RaC MDSCs were an independent prognostic factor of reduced OS. On the contrary, longer OS was associated to low levels of the proinflammatory proteins IL-6 and CRP and tumorassociated factors S100B and LDH both at baseline and after treatment. Increasing number of total T cells and especially of PD-1C T cells were associated with better prognosis, and upregulation of PD-1 C expression on CD4 C T cells upon treatment was associated with lower toxicity. As several parameters were associated to OS, we included these factors in a multivariate survival model, and we identified IL-6 and ECOG PS as independent biomarkers associated with improved OS, whereas high levels of LDH and CD14 C /IL4RaC MDSCs were negative independent markers of reduced OS.

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Section: Discussionmentioning

confidence: 99%

Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab

et al. 2016

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“…52 Another study reported that circulating CD33 + CD11b + HLA-DR − MDSCs from peripheral blood can be used as biomarkers to predict response and survival of stage IV melanoma patients in ipilimumab treatments. 53 Low levels of MDSCs prior to CTLA-4 therapy correlated with an objective clinical response, long-term survival, and improved clinical status. The presence of more than 55.5% of circulating CD33 + CD11b + out of the HLA-DR − cells in 56 patients was associated with significantly short OS (p < 0.003), a median of 6.5 months, in comparison to the group showing lower MDSC frequencies, with a median survival of 15.6 months.…”

Section: Predictive Markers Of Anti-ctla-4 Therapymentioning

confidence: 93%

Highlights on immune checkpoint inhibitors in non–small cell lung cancer

Shen

Ren²

2017

Tumour Biol.

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The treatment of advanced or refractory non-small cell lung cancer has been historically difficult owing to the lack of studies on effective systemic cure. The progress in lung cancer treatment has plateaued, necessitating new options for additional benefits. Immune checkpoint proteins are co-inhibitory factors that can diminish the antigen-specific immune responses by attenuating the regulatory role of cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, lymphocyte-activation gene 3, and T-cell immunoglobulin mucin-3. The therapeutic strategies targeting immune checkpoints mainly focus on the monoclonal antibody of these regulatory factors, which may facilitate clinical decision making. An enhanced understanding of the drug-resistance mechanisms and the therapeutic efficacy regulation will provide opportunities to improve the clinical outcomes of non-small cell lung cancer patients. Preclinical and clinical trials on these key immune-regulatory agents, which has heralded a new era in immuno-oncology in non-small cell lung cancer treatment, are currently in development. KeywordsNon-small cell lung cancer, immune checkpoint, cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, programmed cell death ligand-1, tumor immunotherapy Date

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“…Thus, in melanoma patients treated with Ipilimumab, decreased amounts and immunosuppressive functionality of both monocytic and polymorphonuclear MDSCs correlated with beneficial therapeutic effects [65,131,135,136,137]. Moreover, non-responding patients showed also elevated serum levels of inflammatory molecules S100A8/A9 and high mobility group box 1 (HMGB1), suggesting that MDSC and chronic inflammatory factors can be not only therapeutic targets in cancer patients but also serve as new biomarkers detecting the group of advanced melanoma patients who may benefit from Ipilimumab therapy [135].…”

Section: Neutralizing Immunosuppression Induced By Mdscsmentioning

confidence: 99%

The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

et al. 2016

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The immunosuppressive tumor microenvironment represents not only one of the key factors stimulating tumor progression but also a strong obstacle for efficient tumor immunotherapy. Immunosuppression was found to be associated with chronic inflammatory mediators including cytokines, chemokines and growth factors produced by cancer and stroma cells. Long-term intensive production of these factors induces the formation of myeloid-derived suppressor cells (MDSCs) representing one of the most important players mediating immunosuppression. Moreover, MDSCs could not only inhibit anti-tumor immune reactions but also directly stimulate tumor growth and metastasis. Therefore, understanding the mechanisms of their generation, expansion, recruitment and activation is required for the development of novel strategies for tumor immunotherapy.

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Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

Abstract: Purpose: High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33 þ

Cited by 173 publications

References 43 publications

Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab

Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab

Highlights on immune checkpoint inhibitors in non–small cell lung cancer

The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

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