RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000405
DO 10.1136/jitc-2019-000405
VO 8
IS 1
A1 Kyle G Mitchell
A1 Lixia Diao
A1 Tatiana Karpinets
A1 Marcelo V Negrao
A1 Hai T Tran
A1 Edwin R Parra
A1 Erin M Corsini
A1 Alexandre Reuben
A1 Lorenzo Federico
A1 Chantale Bernatchez
A1 Hitoshi Dejima
A1 Alejandro Francisco-Cruz
A1 Jing Wang
A1 Mara B Antonoff
A1 Ara A Vaporciyan
A1 Stephen G Swisher
A1 Tina Cascone
A1 Ignacio I Wistuba
A1 John V Heymach
A1 Don L Gibbons
A1 Jianjun Zhang
A1 Cara L Haymaker
A1 Boris Sepesi
YR 2020
UL http://jitc.bmj.com/content/8/1/e000405.abstract
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.