PT  - JOURNAL ARTICLE
AU  - Kyle G Mitchell
AU  - Lixia Diao
AU  - Tatiana Karpinets
AU  - Marcelo V Negrao
AU  - Hai T Tran
AU  - Edwin R Parra
AU  - Erin M Corsini
AU  - Alexandre Reuben
AU  - Lorenzo Federico
AU  - Chantale Bernatchez
AU  - Hitoshi Dejima
AU  - Alejandro Francisco-Cruz
AU  - Jing Wang
AU  - Mara B Antonoff
AU  - Ara A Vaporciyan
AU  - Stephen G Swisher
AU  - Tina Cascone
AU  - Ignacio I Wistuba
AU  - John V Heymach
AU  - Don L Gibbons
AU  - Jianjun Zhang
AU  - Cara L Haymaker
AU  - Boris Sepesi
TI  - 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
AID  - 10.1136/jitc-2019-000405
DP  - 2020 Apr 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000405
VI  - 8
IP  - 1
4099  - http://jitc.bmj.com/content/8/1/e000405.short
4100  - http://jitc.bmj.com/content/8/1/e000405.full
SO  - J Immunother Cancer2020 Apr 01; 8
AB  - 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-1β, IL-17A, TNFα, IL-6) and TH2-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 IFNγ-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.