Neutrophil expansion defines an immunoinhibitory peripheral and intratumoral inflammatory milieu in resected non-small cell lung cancer: a descriptive analysis of a prospectively immunoprofiled cohort
Open Access
- 1 January 2020
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (1), e000405
- https://doi.org/10.1136/jitc-2019-000405
Abstract
Background The biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between circulating and intratumoral neutrophil populations and features of the immune contexture in patients undergoing NSCLC resection. Methods Preoperative soluble cytokine and angiogenic factors; tumor multiplex immunofluorescence; RNA, whole exome, and T-cell receptor sequencing; and flow cytometry were analyzed for relationships with populations of circulating (from complete blood counts) and intratumoral neutrophils (transcriptional signatures) in a prospectively enrolled resected NSCLC cohort (n=66). In a historical cohort (n=1524), preoperative circulating neutrophil and lymphocyte counts were analyzed for associations with overall survival (OS). Results Circulating neutrophil populations were positively correlated with increased tumor burden, and surgical tumor resection was followed by a subsequent reduction in peripheral neutrophil counts. Expansion of the circulating neutrophil compartment was associated with increased levels of pro-granulopoietic (IL-1 beta, IL-17A, TNF alpha, IL-6) and T(H)2-associated (IL-5, IL-13) cytokines. Tumors with high intratumoral neutrophil burden were marked by a blunted T-cell response characterized by reduced expression of cytotoxic T-cell genes (CD8A, CD8B, GZMA, GZMB), decreased CD3(+)CD8(+) cell infiltration, and diminished expression of IFN gamma-related genes. The associations between increased intratumoral neutrophil burden and reduced CD3(+)CD8(+) infiltration persisted after adjustment for tumor size, histology, mutational burden, and PD-L1 expression. In 1524 patients, elevated preoperative circulating neutrophil count was independently associated with worse OS (main effect HR 1.82, 95% CI 1.24 to 2.68, p=0.002). Conclusions Our findings demonstrate that neutrophil expansion reflects protumorigenic and immunosuppressive processes that manifest as worse OS in patients undergoing NSCLC resection. These results justify further investigation of therapeutic strategies targeting neutrophil-associated immune evasion.Funding Information
- University of Texas MD Anderson Cancer Center (Moon Shot Lung Cancer Moon Shots Program)
- Lung SPORE (P50CA070907)
- CCSG (P30CA016672)
This publication has 48 references indexed in Scilit:
- Sensitive detection of somatic point mutations in impure and heterogeneous cancer samplesNature Biotechnology, 2013
- Effect of Low-Fat Diets on Plasma Levels of NF-κB–Regulated Inflammatory Cytokines and Angiogenic Factors in Men with Prostate CancerCancer Prevention Research, 2011
- Molecular signatures database (MSigDB) 3.0Bioinformatics, 2011
- Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non–Small-Cell Lung CancerJournal of Clinical Oncology, 2010
- Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cellsBlood, 2009
- The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humansJCI Insight, 2009
- Interleukin-1 and IL-23 Induce Innate IL-17 Production from γδ T Cells, Amplifying Th17 Responses and AutoimmunityImmunity, 2009
- Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short readsBioinformatics, 2009
- Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencingNature Biotechnology, 2009
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005