A Novel Paradigm Between Leukocytosis, G-CSF Secretion, Neutrophil-to-Lymphocyte Ratio, Myeloid-Derived Suppressor Cells, and Prognosis in Non-small Cell Lung Cancer

Tavakkoli, Montreh; Wilkins, Cy; Mones, Jodi V.; Mauro, Michael J.

doi:10.3389/fonc.2019.00295

Cited by 56 publications

(47 citation statements)

References 42 publications

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“…Increasing evidence has indicated that some types of established cancers may actually accelerate the process of myelopoiesis, resulting in moderate, or even profound, leukocytosis, characterized by increased numbers of immature myeloid cells in the bone marrow, blood and spleen [25][26][27][28][29]. In this setting, accelerated myelopoiesis appears to result from the production of bone marrow-stimulating growth factors by tumor cells, most notably the cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) [30][31][32][33][34][35]. In this context, it is noteworthy that an increased circulating neutrophil/lymphocyte ratio (NLR, defined as the absolute circulating neutrophil count divided by the lymphocyte count) is widely regarded as being a negative prognostic indicator in many, but not all, types of cancer reviewed in [36].…”

Section: Recruitment and Exploitation Of Neutrophils By Tumorsmentioning

confidence: 99%

“…Targeting of the G-CSF/MDSC axis is an attractive option [35], which is attainable in the experimental setting via the administration of mAbs that neutralize G-CSF directly or block its receptor expressed on bone marrow precursor cells [129]. However, such a strategy is impractical in the clinical setting since it presents an unacceptably high risk of severe neutropenia and development of life-threatening microbial infection.…”

Section: Cytokine Targetingmentioning

confidence: 99%

“…Clearly, the clinical utility of all of the aforementioned MDSC-targeted, adjunctive anti-cancer therapies (summarized in Table 4) remains to be established, with CXCR1/2 antagonists seemingly the most promising. [35,129] mAb targeting of IL-17A or its receptor Promising pre-clinical findings in colorectal, breast and non-small cell lung cancers [40,131,132] Macrolide antibiotic targeting of IL-8 and IL-17A production Uncertain [135] mAb targeting of TGFβ1 Promising, but poses the risk of dysregulated immune homeostasis [59] Administration of type I interferons to prevent N1→N2 TAN reprogramming…”

Section: Other Strategiesmentioning

confidence: 99%

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Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

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Section: Recruitment and Exploitation Of Neutrophils By Tumorsmentioning

confidence: 99%

Section: Cytokine Targetingmentioning

confidence: 99%

Section: Other Strategiesmentioning

confidence: 99%

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Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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“…Immunosuppressive cells, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T (Treg) cells, act as suppressive TIME components to attenuate immune responses [2]. Among these cells, MDSCs have roles in the prognosis, development, and treatment of LC that have been paid increasing attention [3,4]. MDSCs are a group of highly heterogeneous cells derived from immature myeloid progenitors that are usually divided into two subpopulations: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Myeloid-derived suppressor cells—new and exciting players in lung cancer

et al. 2020

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Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

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“…Additional proposed markers of response include neutrophil‐to‐lymphocyte ratio (NLR), which has been reported to increase over time in non‐responders and decrease in responders, and inflammatory cytokines, which have also been correlated with response rates and toxicity 72–78 (Figure 3). Myeloid‐derived suppressor cell (MDSC) levels have been used to predict therapy response or resistance to ipilimumab treatment in metastatic melanoma patients, where increased frequency was associated with decreased efficacy, and vice versa 79,80 .…”

Section: Novel Ici Approaches To Precision Oncologymentioning

confidence: 99%

Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

Watson

Doi

Hansen

et al. 2020

Brit J Clinical Pharma

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The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune‐oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune‐oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi‐omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient‐specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune‐oncology.

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A Novel Paradigm Between Leukocytosis, G-CSF Secretion, Neutrophil-to-Lymphocyte Ratio, Myeloid-Derived Suppressor Cells, and Prognosis in Non-small Cell Lung Cancer

Cited by 56 publications

References 42 publications

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Myeloid-derived suppressor cells—new and exciting players in lung cancer

Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

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