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Updated: Jan 1, 2026
Isolation and Characterization of Neutrophils with Anti-Tumor Properties
Published on: June 19, 2015
Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC
Julia Kargl1,2, Xiaodong Zhu1, Huajia Zhang1
1Fred Hutchinson Clinical Research Division, Seattle, Washington, USA.
Abstract:
Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.
Insights
Neutrophils hinder immune checkpoint inhibitor (ICI) therapy effectiveness in non-small cell lung cancer (NSCLC). Targeting neutrophils alongside ICI treatment may improve patient outcomes by promoting T cell infiltration and anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) are a first-line therapy for non-small cell lung cancer (NSCLC).
- Most NSCLC patients exhibit resistance to ICI monotherapy, necessitating novel therapeutic strategies.
- Identifying factors that limit T cell infiltration is crucial for overcoming ICI resistance.
Purpose of the Study:
- To identify cellular components that impede CD8+ T cell accumulation in NSCLC.
- To investigate the role of myeloid cells, particularly neutrophils, in ICI resistance.
- To evaluate the CD8+/neutrophil ratio as a predictive biomarker for ICI response.
Main Methods:
- Unbiased analysis of flow cytometry, gene expression, and multiplexed immunohistochemical data from NSCLC patients.
- Assessment of myeloid cell populations and their association with T cell infiltration.
- Evaluation of the CD8+/neutrophil ratio in distinguishing patient subgroups and predicting ICI response in independent cohorts.
- Preclinical studies in tumor-bearing mice combining anti-PD1 and a CXCR1/2 inhibitor (SX-682).
Main Results:
- A myeloid-rich subgroup lacking CD4+ and CD8+ T cells was identified in NSCLC.
- Neutrophils were highly associated with this myeloid phenotype and inversely correlated with T cell presence.
- The CD8+/neutrophil ratio effectively differentiated between ICI-responsive and non-responsive patients.
- Combination therapy in mice led to T cell infiltration into tumors and induced IFN-γ-responsive genes.
Conclusions:
- Neutrophils play a significant role in mediating resistance to ICI therapy in NSCLC.
- The CD8+/neutrophil ratio serves as a potential predictive biomarker for ICI efficacy.
- Neutrophil antagonism, in combination with ICIs, represents a promising strategy to enhance anti-tumor immune responses and improve treatment outcomes in NSCLC.
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