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      Prognostic role of pretreatment circulating MDSCs in patients with solid malignancies: A meta-analysis of 40 studies

      1 , 2 , 1 , 3 , 1 , 1 , 1
      OncoImmunology
      Informa UK Limited

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          Abstract

          <p id="d9097774e237">Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor progression, mainly through immune suppression. Inverse correlations have been observed between MDSC levels and patient survival for various malignancies. The purpose of this meta-analysis was to evaluate the prognostic value of pretreatment circulating MDSCs. We searched MEDLINE and EMBASE from their inceptions to September 2017 to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) were estimated for overall survival (OS) and combined disease-free survival, progression-free survival, and recurrence-free survival (DFS/PFS/RFS). A total of 40 studies comprising 2721 were included. For solid tumors, high levels of pretreatment circulating MDSCs were significantly associated with worse OS (HR = 1.796, 95% CI = 1.587–2.032) and DFS/PFS/RFS (HR = 2.459, 95% CI = 2.018–2.997). Breast cancer showed the largest association between high MDSC levels and worse OS (pooled HR = 3.053). Elevated MDSCs were also associated with worse OS for mixed-stage tumors (pooled HR = 1.659) and advanced-stage tumors (pooled HR = 2.337). Furthermore, both monocytic-MDSCs (M-MDSCs) and granulocytic or polymorphonuclear (PMN-MDSCs) showed negative associations with survival outcomes. Overall, high levels of pretreatment circulating MDSCs negatively influenced survival in most cancers. Pretreatment circulating MDSCs should be taken into account to further improve prognostic evaluation and develop novel therapeutic strategies. </p>

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          Most cited references56

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          Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.

          Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens.
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            Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis.

            Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic. Given that MDSCs are a manifestation of aberrant myelopoiesis, we hypothesized that MDSCs arise from perturbations in the regulation of interferon regulatory factor-8 (IRF-8), an integral transcriptional component of myeloid differentiation and lineage commitment. Overall, we demonstrated that (a) Irf8-deficient mice generated myeloid populations highly homologous to tumor-induced MDSCs with respect to phenotype, function, and gene expression profiles; (b) IRF-8 overexpression in mice attenuated MDSC accumulation and enhanced immunotherapeutic efficacy; (c) the MDSC-inducing factors G-CSF and GM-CSF facilitated IRF-8 downregulation via STAT3- and STAT5-dependent pathways; and (d) IRF-8 levels in MDSCs of breast cancer patients declined with increasing MDSC frequency, implicating IRF-8 as a negative regulator in human MDSC biology. Together, our results reveal a previously unrecognized role for IRF-8 expression in MDSC subset development, which may provide new avenues to target MDSCs in neoplasia.
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              Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab.

              The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.
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                Author and article information

                Journal
                OncoImmunology
                OncoImmunology
                Informa UK Limited
                2162-402X
                August 06 2018
                October 03 2018
                July 30 2018
                October 03 2018
                : 7
                : 10
                : e1494113
                Affiliations
                [1 ] Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
                [2 ] School of Basic Medical Sciences, Capital Medical University, Beijing, China
                [3 ] Department of Neurosurgery, Key Laboratory, The Second Hospital of Yulin, Xi’an Jiao tong University, Xi’an, China
                Article
                10.1080/2162402X.2018.1494113
                6169582
                30288362
                27f67dfb-33ac-422f-a724-3384e563abd4
                © 2018
                History

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