Journal Article
. 2019 May; 9:295.
doi: 10.3389/fonc.2019.00295.

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

Montreh Tavakkoli 1 Cy R Wilkins 2 Jodi V Mones 2 Michael J Mauro 3 
Affiliations
  • PMID: 31080780
  •     41 References
  •     17 citations

Abstract

Leukocytosis is a common feature of malignancies. While controversial, there appears to be an association between the degree of tumor-related leukocytosis and prognosis. In this paper, we provide evidence supporting an untapped clinical paradigm linking G-CSF secretion to the induction of leukocytosis and expansion of myeloid-derived suppressor cells, providing an explanation for the association between leukocytosis, elevated neutrophil-to-lymphocyte ratios and prognosis in non-small cell lung cancer. Clinically validating this mechanism may identify MDSCs and G-CSF as dynamic markers of early disease progression and therapeutic response, and shed light onto novel therapeutic avenues for the treatment of patients with non-small cell lung cancer.

Keywords: NLR; biomarker (development); granulocyte-colony stimulating factor (G-CSF); leukocytosis; myeloid derived suppressor cell (MDSC); neutrophil to lymphocyte ratio (NLR); non-small cell lung cancer; paraneoplastic leukocytosis.

Moderate dose-intensive chemotherapy for patients with non-small cell lung cancer: randomized trial, can it improve survival of patients with good performance status?
M Masutani, I Tsujino, +6 authors, T Horie.
Oncol Rep, 1999 Jul 30; 6(5). PMID: 10425301
Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma.
I Kasuga, S Makino, +3 authors, K Ohyashiki.
Cancer, 2001 Dec 18; 92(9). PMID: 11745296
Granulocyte growth factors in the treatment of non-small cell lung cancer (NSCLC).
Francesco Grossi, Marcello Tiseo.
Crit Rev Oncol Hematol, 2006 May 16; 58(3). PMID: 16697211
Review.
A prognostic model for advanced stage nonsmall cell lung cancer. Pooled analysis of North Central Cancer Treatment Group trials.
Sumithra J Mandrekar, Steven E Schild, +9 authors, James R Jett.
Cancer, 2006 Jul 19; 107(4). PMID: 16847887
Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.
J Crawford, H Ozer, +7 authors, G Rausch.
N Engl J Med, 1991 Jul 18; 325(3). PMID: 1711156
Highly Cited.
Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer.
J N H Timmer-Bonte, C J A Punt, +5 authors, V C G Tjan-Heijnen.
Lung Cancer, 2007 Nov 17; 60(2). PMID: 18006110
Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy.
C Marcela Diaz-Montero, Mohamed Labib Salem, +3 authors, Alberto J Montero.
Cancer Immunol Immunother, 2008 May 01; 58(1). PMID: 18446337    Free PMC article.
Highly Cited.
Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells.
Farbod Shojaei, Napoleone Ferrara.
Cancer Res, 2008 Jul 18; 68(14). PMID: 18632597
Review.
G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models.
Farbod Shojaei, Xiumin Wu, +5 authors, Napoleone Ferrara.
Proc Natl Acad Sci U S A, 2009 Apr 07; 106(16). PMID: 19346489    Free PMC article.
Highly Cited.
Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study.
John M Granger, Dimitrios P Kontoyiannis.
Cancer, 2009 Jun 25; 115(17). PMID: 19551882
Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14⁻/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer.
Chien-Ying Liu, Yu-Min Wang, +13 authors, Han-Pin Kuo.
J Cancer Res Clin Oncol, 2009 Jul 03; 136(1). PMID: 19572148
Highly Cited.
Granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) as potential tumor markers in non small cell lung cancer diagnosis.
Burak Bahar, Banu Acedil Ayc Iota, +3 authors, Ramazan Yildiz.
Asian Pac J Cancer Prev, 2010 Nov 03; 11(3). PMID: 21039040
Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes.
Marcin Kowanetz, Xiumin Wu, +18 authors, Napoleone Ferrara.
Proc Natl Acad Sci U S A, 2010 Nov 18; 107(50). PMID: 21081700    Free PMC article.
Highly Cited.
Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer.
G P Stathopoulos, A Armakolas, +3 authors, H Chandrinou.
Oncol Rep, 2011 Mar 25; 25(6). PMID: 21431281
CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer.
Po-Hao Feng, Kang-Yun Lee, +11 authors, Han-Pin Kuo.
Am J Respir Crit Care Med, 2012 Sep 08; 186(10). PMID: 22955317    Free PMC article.
Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients.
Ang Huang, Bo Zhang, +3 authors, Ya-Jun Guo.
Cancer Immunol Immunother, 2013 Jun 14; 62(9). PMID: 23760662
Highly Cited.
Myeloid-derived suppressor cells in the development of lung cancer.
Myrna L Ortiz, Lily Lu, Indu Ramachandran, Dmitry I Gabrilovich.
Cancer Immunol Res, 2014 Apr 30; 2(1). PMID: 24778162    Free PMC article.
A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients.
Eleni-Kyriaki Vetsika, Filippos Koinis, +6 authors, Athanasios Kotsakis.
J Immunol Res, 2014 Dec 02; 2014. PMID: 25436215    Free PMC article.
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.
Julie Brahmer, Karen L Reckamp, +22 authors, David R Spigel.
N Engl J Med, 2015 Jun 02; 373(2). PMID: 26028407    Free PMC article.
Highly Cited.
Prognostic significance of neutrophil-to-lymphocyte ratio in non-small cell lung cancer: a meta-analysis.
Xiao-Bin Gu, Tian Tian, Xiao-Jing Tian, Xiao-Jun Zhang.
Sci Rep, 2015 Jul 25; 5. PMID: 26205001    Free PMC article.
Highly Cited.
Reduction of Inappropriate Prophylactic Pegylated Granulocyte Colony-Stimulating Factor Use for Patients With Non-Small-Cell Lung Cancer Who Receive Chemotherapy: An ASCO Quality Training Program Project of the Cleveland Clinic Taussig Cancer Institute.
Lindsey Martin Goodman, Machelle B Moeller, +8 authors, James P Stevenson.
J Oncol Pract, 2016 Jan 14; 12(1). PMID: 26759474
Effect of First-Line Treatment on Myeloid-Derived Suppressor Cells' Subpopulations in the Peripheral Blood of Patients with Non-Small Cell Lung Cancer.
Filippos Koinis, Eleni Kyriaki Vetsika, +5 authors, Athanasios Kotsakis.
J Thorac Oncol, 2016 May 15; 11(8). PMID: 27178984
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.
Martin Reck, Delvys Rodríguez-Abreu, +16 authors, KEYNOTE-024 Investigators.
N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718847
Highly Cited.
Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody.
Koung Jin Suh, Se Hyun Kim, +6 authors, Jong Seok Lee.
Cancer Immunol Immunother, 2017 Dec 06; 67(3). PMID: 29204702
Developing a Predictive Model for Clinical Outcomes of Advanced Non-Small Cell Lung Cancer Patients Treated With Nivolumab.
Wungki Park, Deukwoo Kwon, +13 authors, Mohammad Jahanzeb.
Clin Lung Cancer, 2018 Jan 18; 19(3). PMID: 29336998
Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis.
Danielle Benedict Sacdalan, Josephine Anne Lucero, Dennis Lee Sacdalan.
Onco Targets Ther, 2018 Mar 06; 11. PMID: 29503570    Free PMC article.
Highly Cited. Review.
Circulating and Tumor Myeloid-derived Suppressor Cells in Resectable Non-Small Cell Lung Cancer.
Yoshikane Yamauchi, Seyer Safi, +13 authors, Viktor Umansky.
Am J Respir Crit Care Med, 2018 Apr 05; 198(6). PMID: 29617574
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
Matthew D Hellmann, Tudor-Eliade Ciuleanu, +21 authors, Luis Paz-Ares.
N Engl J Med, 2018 Apr 17; 378(22). PMID: 29658845    Free PMC article.
Highly Cited.
Correlation of Neutrophil to Lymphocyte Ratio and Absolute Neutrophil Count With Outcomes With PD-1 Axis Inhibitors in Patients With Advanced Non-Small-Cell Lung Cancer.
Alona Zer, Mike R Sung, +11 authors, Natasha B Leighl.
Clin Lung Cancer, 2018 May 29; 19(5). PMID: 29803574
Highly Cited.
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
Mark A Socinski, Robert M Jotte, +18 authors, IMpower150 Study Group.
N Engl J Med, 2018 Jun 05; 378(24). PMID: 29863955
Highly Cited.
Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.
Rebekka Weber, Viktor Fleming, +5 authors, Viktor Umansky.
Front Immunol, 2018 Jun 27; 9. PMID: 29942309    Free PMC article.
Highly Cited. Review.
Neutrophil-to-lymphocyte ratio after four weeks of nivolumab administration as a predictive marker in patients with pretreated non-small-cell lung cancer.
Takayuki Takeda, Mayumi Takeuchi, Masahiko Saitoh, Sorou Takeda.
Thorac Cancer, 2018 Aug 21; 9(10). PMID: 30126063    Free PMC article.
Blood immune cell biomarkers in lung cancer.
D Riemann, M Cwikowski, +4 authors, B Seliger.
Clin Exp Immunol, 2018 Sep 25; 195(2). PMID: 30246868    Free PMC article.
The Ratio of Peripheral Regulatory T Cells to Lox-1+ Polymorphonuclear Myeloid-derived Suppressor Cells Predicts the Early Response to Anti-PD-1 Therapy in Patients with Non-Small Cell Lung Cancer.
Hye Ryun Kim, Su-Myeong Park, +7 authors, Je-In Youn.
Am J Respir Crit Care Med, 2018 Oct 20; 199(2). PMID: 30339766    Free PMC article.
Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study.
Shirish M Gadgeel, James P Stevenson, +12 authors, Vassiliki Papadimitrakopoulou.
Lung Cancer, 2018 Nov 16; 125. PMID: 30429032    Free PMC article.
Dynamics of blood neutrophil-related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non-small cell lung cancer: A hypothesis-generating study.
Hiroshi Soda, Daiki Ogawara, +9 authors, Hiroshi Mukae.
Thorac Cancer, 2018 Dec 26; 10(2). PMID: 30582295    Free PMC article.
Leukocyte concentrations in discrimination of benign from malignant lung lesions.
S P Thomson, J F Kessler, T P Miller.
Am J Med, 1986 Jun 01; 80(6). PMID: 3728502
Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer.
P J Woll, J Hodgetts, +3 authors, N Thatcher.
J Clin Oncol, 1995 Mar 01; 13(3). PMID: 7533825
Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy.
V Trillet-Lenoir, J Green, +7 authors, D Tomita.
Eur J Cancer, 1993 Jan 01; 29A(3). PMID: 7691119
Highly Cited.
Efficacy of recombinant human granulocyte-macrophage colony-stimulating factor for chemotherapy-induced leukopenia in patients with non-small-cell lung cancer.
K Eguchi, J Kabe, +7 authors, T Uzawa.
Cancer Chemother Pharmacol, 1994 Jan 01; 34(1). PMID: 8174201
Serum levels of cytokines in patients with untreated primary lung cancer.
N Katsumata, K Eguchi, +6 authors, N Saijo.
Clin Cancer Res, 1996 Mar 01; 2(3). PMID: 9816203
Doxorubicin-polyglycerol-nanodiamond conjugate is a cytostatic agent that evades chemoresistance and reverses cancer-induced immunosuppression in triple-negative breast cancer.
Shen-Jun Yuan, Yong-Hong Xu, +6 authors, Xiao Chen.
J Nanobiotechnology, 2019 Oct 19; 17(1). PMID: 31623629    Free PMC article.
Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC) and malignant mesothelioma: therapeutic implications.
Albert D Donnenberg, James D Luketich, Vera S Donnenberg.
Oncotarget, 2019 Nov 20; 10(60). PMID: 31741710    Free PMC article.
Myeloid-derived suppressor cells-new and exciting players in lung cancer.
Zhenzhen Yang, Jiacheng Guo, +3 authors, Wang Ma.
J Hematol Oncol, 2020 Feb 02; 13(1). PMID: 32005273    Free PMC article.
Review.
Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study.
Els Verdegaal, Monique K van der Kooij, +11 authors, Sjoerd H van der Burg.
J Immunother Cancer, 2020 Apr 03; 8(1). PMID: 32238469    Free PMC article.
Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy.
Bernardo L Rapoport, Helen C Steel, +2 authors, Ronald Anderson.
Molecules, 2020 Apr 05; 25(7). PMID: 32244751    Free PMC article.
Review.
Granulocyte Colony-Stimulating Factor Attenuates Renal Ischemia-Reperfusion Injury by Inducing Myeloid-Derived Suppressor Cells.
Ji-Jing Yan, Jung-Hwa Ryu, +7 authors, Jaeseok Yang.
J Am Soc Nephrol, 2020 Mar 07; 31(4). PMID: 32132198    Free PMC article.
Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?
Geoffrey Alan Watson, Jeffrey Doi, Aaron Richard Hansen, Anna Spreafico.
Br J Clin Pharmacol, 2020 May 13; 86(9). PMID: 32394468    Free PMC article.
Review.
Neutrophil-to-lymphocyte ratio in combination with PD-L1 or lactate dehydrogenase as biomarkers for high PD-L1 non-small cell lung cancer treated with first-line pembrolizumab.
Giuseppe Luigi Banna, Diego Signorelli, +8 authors, Alfredo Addeo.
Transl Lung Cancer Res, 2020 Sep 22; 9(4). PMID: 32953525    Free PMC article.
Genomic analysis of the prognostic value of colony-stimulating factors (CSFs) and colony-stimulating factor receptors (CSFRs) across 24 solid cancer types.
Xinyi Huang, Pingping Hu, Jiandong Zhang.
Ann Transl Med, 2020 Sep 22; 8(16). PMID: 32953794    Free PMC article.
Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8.
Markus Hecht, Antoniu Oreste Gostian, +18 authors, Rainer Fietkau.
J Immunother Cancer, 2020 Oct 08; 8(2). PMID: 33023982    Free PMC article.
Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer.
Annette J Theron, Helen C Steel, Bernardo L Rapoport, Ronald Anderson.
Pharmaceuticals (Basel), 2020 Nov 26; 13(11). PMID: 33233675    Free PMC article.
Review.
The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.
G L Banna, A Cortellini, +43 authors, A Addeo.
ESMO Open, 2021 Mar 19; 6(2). PMID: 33735802    Free PMC article.
Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy.
Nicole K Yun, Sherin J Rouhani, +7 authors, Mary Jo Fidler.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33804721    Free PMC article.
Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors.
Andrew Dunbar, Kelly L Bolton, +17 authors, Simon Mantha.
Blood, 2020 Dec 04; 137(15). PMID: 33270827    Free PMC article.
Mechanisms Underlying the Role of Myeloid-Derived Suppressor Cells in Clinical Diseases: Good or Bad.
Yongtong Ge, Dalei Cheng, +2 authors, Junfeng Zhang.
Immune Netw, 2021 Jul 20; 21(3). PMID: 34277111    Free PMC article.
Review.
Paraneoplastic Leukemoid Reaction after Primary Tumor Resection in Patients with Urothelial Carcinoma: A Report of 2 Cases.
Shien-Tung Pan, Shu-Ping Tseng, Chiou-Huey Wang, Yu-Ting Chou.
Clin Pathol, 2021 Jul 23; 14. PMID: 34291205    Free PMC article.
Diagnostic and prognostic biomarkers in oligometastatic non-small cell lung cancer: a literature review.
Diego Cortinovis, Umberto Malapelle, +4 authors, Christian Rolfo.
Transl Lung Cancer Res, 2021 Aug 26; 10(7). PMID: 34430374    Free PMC article.
Review.