Intratumoral neutrophil-to-lymphocyte ratio is mirrored by circulating neutrophil-to-lymphocyte ratio in nonsmall cell lung cancer - Abstract and study findings

Sep 23, 2026

Tumor-initiated emergency granulopoiesis expands circulating neutrophils and supports recruitment into the tumor microenvironment (TME), potentially promoting progression. Although elevated circulating neutrophil-to-lymphocyte ratio (cNLR) predicts worse outcomes in non-small cell lung cancer (NSCLC), the extent to which this reflects neutrophil abundance within tumors remains unclear. The study links cNLR with intratumoral NLR (tNLR), explores proteogenomic and immune associations, and evaluates prognostic impact across cohorts.

LanguageEnglish

CategoryHealthcare

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Pages8

Reading Time20 min

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Abstract

Study design and cohorts

Key findings: correlations and prognosis

Mechanistic and immunologic associations

Open access Short report Intratumoral neutrophil-to-lymphocyte ratio is mirrored by circulating neutrophil-to-lymphocyte ratio in nonsmall cell lung cancer Kyle G. Mitchell ,1 Younghee Lee,2 Nathaniel Deboever,1 Marcelo V Negrao 3 , Hai T Tran,3 Edwin Parra,2 Lauren Byers,3 Alexandre Reuben ,3 Lorenzo Federico,4,5 Chantale Bernatchez,4 Jing Wang,6 Mara B Antonoff,1 Ara A Vaporciyan,1 Stephen G Swisher,1 Tina Cascone ,3 Ignacio I Wistuba,2 John V Heymach,3 Don L Gibbons,3,7 Jianjun Zhang ,3 Daniel J McGrail ,8,9 Boris Sepesi,10 Cara L Haymaker 2 To cite: Mitchell KG, Lee Y, Deboever N, et al. Intratumoral neutrophil-to-lymphocyte ratio is mirrored by circulating neutrophil-to-lymphocyte ratio in non-small cell lung cancer. Journal for ImmunoTherapy of Cancer 2025;13:e011458 . doi:10.1136/jitc-2025-011458 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2025-011458](jitc-2025-011458)) . Accepted 26 May 2025 © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. For numbered affiliations see end of article. Correspondence to Dr Cara L Haymaker; [CHaymaker@mdanderson.org](CHaymaker@mdanderson.org) Dr Boris Sepesi; boris.sepesi@hcahealthcare. com Dr Daniel J McGrail; [mcgraid@ccf.org](mcgraid@ccf.org) ABSTRACT Tumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis. We analyzed tNLR (transcriptomic signatures) and cNLR in a prospectively-enrolled cohort of patients with NSCLC (stage IA-III) that was subjected to multifaceted immunoprofiling (ImmunogenomiC prOfiling of earlystage Non-small cell lung cancer (ICON), N=150) . We examined the relationship between tNLR and genomic, transcriptomic, and proteomic features of NSCLC tumorsin The Cancer Genome Atlas (TCGA) and ICON. Finally, tNLR was analyzed for associations with postoperative recurrence-free survival (ICON) and overall survival (TCGA) . In the ICON cohort, tNLR was significantly positively correlated with cNLR, but there was no association between intratumoral and circulating neutrophils or lymphocytes alone. High tNLR was associated with poor postoperative recurrence-free survival, and multivariate analysis indicated tNLR was a stronger driver of outcomes than cNLR. Mutations in KEAP1, STK11, PTEN, PI3K, and TSC2 were associated with an increased tNLR. Tumors with elevated tNLR were marked by proteomic and transcriptomic features indicative of increased cell cycle, receptor tyrosine kinase, and YAP signaling, as well as immunosuppression (reduced IFNG and GZMB expression) . Flow cytometry and multiplex immunofluorescence confirmed reduced CD8+granzyme B+ T cells in the TME of tumors with high tNLR. Finally, TCGA confirmed associations between tNLR with prognosis, mutational status, and proteomic/transcriptomic features, and further showed that tNLR is prognostically relevant in multiple solid cancers. tNLR is mirrored by NLR in circulation (cNLR) in NSCLCs. High tNLR is associated with an immunosuppressed TME phenotype and poor prognosis across multiple cancers. These findings support ongoing investigations o

FAQs

What is the purpose of comparing cNLR and tNLR in NSCLC?

The study determines whether an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) reflects a similar relative neutrophil abundance within tumors measured by intratumoral NLR (tNLR).

How does tNLR relate to prognosis and postoperative outcomes?

High tNLR is associated with poor postoperative recurrence-free survival, and multivariate analysis indicates tNLR is a stronger driver of outcomes than cNLR.

Which tumor and signaling features are linked to higher tNLR?

Increased tNLR is associated with mutations in KEAP1, STK11, PTEN, PI3K, and TSC2, and tumors show proteomic and transcriptomic features consistent with increased cell cycle, receptor tyrosine kinase, and YAP signaling plus immunosuppression.

Sep 23, 2026

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