HMGB1 Enhances Immune Suppression by Facilitating the Differentiation and Suppressive Activity of Myeloid-Derived Suppressor Cells

Parker, Katherine H.; Sinha, Pratima; Horn, Lucas A.; Clements, Virginia K.; Yang, Huan; Li, Jianhua; Tracey, Kevin J.; Ostrand‐Rosenberg, Suzanne

doi:10.1158/0008-5472.can-13-2347

Cited by 204 publications

(180 citation statements)

References 48 publications

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“…Therefore, we studied in the course of Ipi therapy soluble inflammatory factors, such as S100A8/A9 and HMGB1, that are known to activate and attract MDSC to the tumor site (17)(18)(19) as well as eotaxin-1 (CCL11) that was reported to play a critical role in the recruitment of eosinophils (20). We detected a pronounced upregulation of serum levels of both S100A8/A9 and HMGB1 in nonresponding patients already after the first Ipi infusion (P < 0.05; Fig.…”

Section: Resultsmentioning

confidence: 99%

Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

Gebhardt

Sevko

Jiang

et al. 2015

Clinical Cancer Research

319

228

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Purpose: Immunotherapy with ipilimumab improves the survival of patients with metastatic melanoma. Because only around 20% of patients experience long-term benefit, reliable markers are needed to predict a clinical response. Therefore, we sought to determine if some myeloid cells and related inflammatory mediators could serve as predictive factors for the patients' response to ipilimumab.Experimental Design: We performed an analysis of myeloid cells in the peripheral blood of 59 stage IV melanoma patients before the treatment and at different time points upon the therapy using a clinical laboratory analysis and multicolor flow cytometry. In addition, the production of related inflammatory factors was evaluated by ELISA or Bio-Plex assays.Results: An early increase in eosinophil count during the treatment with ipilimumab was associated with an improved clinical response. In contrast, elevated amounts of monocytic myeloid-derived suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders (n ¼ 36) as compared with basal levels and with responding patients (n ¼ 23). Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders, suggesting their enhanced immunosuppressive capacity. Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.Conclusions: These findings highlight additional mechanisms of ipilimumab effects and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. Ó2015 AACR.

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Section: Resultsmentioning

confidence: 99%

Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

Gebhardt

Sevko

Jiang

et al. 2015

Clinical Cancer Research

319

228

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“…Loss of CD24 releases HMGB1, which is known to stimulate MDSC differentiation in circulation. 12,55 In the 4-NQO model, CD24 was knocked out globally, including from the epithelial cells and the immune cells. We did not specifically address whether the increased oncogenesis was due to the lack of CD24 in the epithelium, the immune system, or both.…”

Section: Discussionmentioning

confidence: 99%

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

et al. 2016

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CD24 expression has been implicated in the oncogenesis of multiple types of cancer and high tumor expression is considered a poor prognosis factor; however, the role of CD24 in oral cancer progression is unknown. Unlike other cancer types, we found that higher CD24 levels in human oral cancers are correlated to lower clinical stage and better overall survival. We then dissected the role of CD24 and mechanisms in oral cancer pathogenesis in mice using a genetic strategy and demonstrated that CD24 deficiency increased the oral cavity tumor burden in response to the carcinogen 4-nitroquioline 1-oxide (4-NQO). Immune profile analysis showed a significant expansion as well as increased suppressive function of myeloid-derived suppressor cells (MDSCs) in CD24 ¡/¡ mice, but no apparent impairment in T cells, B cells, or dendritic cells. Further, studies with an orthotopically transplanted syngeneic squamous carcinoma model in the tongue of CD24 ¡/¡ and CD24 C/¡ mice confirmed the protective roles of CD24 against cancer. Moreover, the difference in tumor growth between CD24 ¡/¡ and CD24 C/¡ mice was blunted by immunodepletion of MDSCs. We conclude that CD24 expression impedes MDSC expansion and function, and thus slows oral cancer oncogenesis. This study is the first to examine the role of CD24 in a de novo oral cancer model, and it highlights the need to consider the immune regulatory roles of CD24 in the development of CD24-targeted therapy for cancer.

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“…HMGB1 promotes the development of MDSCs and contributes to their ability to suppress antigen-driven activation of T cells (77). Overexpression of PPARγ resulted in expansion of PMN-MDSCs with immunosuppressive activity.…”

Section: Gr1mentioning

confidence: 99%

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

Marvel¹,

Gabrilovich²

2015

Journal of Clinical Investigation

888

811

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, respectively).Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.

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HMGB1 Enhances Immune Suppression by Facilitating the Differentiation and Suppressive Activity of Myeloid-Derived Suppressor Cells

Cited by 204 publications

References 48 publications

Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

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