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Updated: Oct 21, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC
Weijie Ma1, Jie Zeng1,2, Shuai Chen3
1Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, California, 95817, USA.
Background:
Lack of biomarkers and in vitro models has contributed to inadequate understanding of the mechanisms underlying the inferior clinical response to immune checkpoint inhibitors (ICIs) in patients with oncogene-driven non-small cell lung cancer (NSCLC).
Methods:
The effect of small molecule tyrosine kinase inhibitors (TKIs) on peripheral blood mononuclear cells (PBMCs) in 34 patients with oncogene-driven NSCLC (cohort A) was compared with those from 35 NSCLC patients without oncogene-driven mutations received ICI (cohort B) or from 22 treatment-naïve NSCLC patients (cohort C). Data for each blood biomarker were summarized by mean and standard deviation and compared by Wilcoxon rank sum tests or Kruskal-Wallis tests with significance at 2-sided p value < 0.05. Co-culture of PBMCs and pleural effusion-derived tumor cells from individual patients with oncogene-driven NSCLC was used to determine the in vitro cytotoxicity of TKI and ICI.
Results:
Except for low CD3% in cohort A, there were no significant differences in other 12 blood biomarkers among the 3 cohorts at baseline. TKI treatment in cohort A was associated with significant increase in CD3% and decrease in total and absolute neutrophils (p < 0.05). In cohort B, patients with good clinical response to ICI treatment (N = 18) had significant increases in absolute lymphocyte counts (ALCs), CD4 and/or CD8 cell counts. Conversely, those patients with poor clinical response to ICI (N = 17) had significant decreases in these cell counts. Of the 27 patients with pre- and post-treatment blood samples in cohort A, 11 had poor clinical response to TKIs and decreased lymphocyte counts. Of the remaining 16 patients who had good clinical response to TKI therapy, 10 (62.5%) patients had decreased, and 6 (37.5%) patients had increased lymphocyte counts. Multicolor immunophenotyping of PBMCs revealed ICI treatment activated additional immune cell types that need further validation. We confirmed that TKI treatment could either antagonize or enhance the effect of ICIs in the co-culture assay using patient's tumor cells and PBMCs.
Conclusions:
To the best of our knowledge, this is the first study showing that TKIs can have various effects on blood immune cells, which may affect their response to ICIs. Further validation of the blood biomarker and in vitro assay is warranted.
Insights
Tyrosine kinase inhibitors (TKIs) can alter immune cell responses, potentially impacting the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Further research is needed to validate these findings and develop predictive biomarkers.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Understanding the mechanisms behind poor response to immune checkpoint inhibitors (ICIs) in oncogene-driven non-small cell lung cancer (NSCLC) is limited by a lack of biomarkers and in vitro models.
- Investigating the interplay between targeted therapies and immunotherapy is crucial for improving treatment outcomes in NSCLC.
Purpose of the Study:
- To investigate the effects of tyrosine kinase inhibitors (TKIs) on peripheral blood mononuclear cells (PBMCs) in patients with oncogene-driven NSCLC.
- To compare these effects with those in NSCLC patients receiving ICIs or treatment-naïve patients.
- To explore the in vitro impact of TKIs and ICIs on cancer cells and immune cells.
Main Methods:
- Comparative analysis of blood biomarkers in three cohorts of NSCLC patients: oncogene-driven treated with TKIs (cohort A), non-oncogene-driven treated with ICIs (cohort B), and treatment-naïve (cohort C).
- Statistical comparison of biomarker data using Wilcoxon rank sum tests or Kruskal-Wallis tests.
- In vitro co-culture assays using patient-derived PBMCs and tumor cells to assess TKI and ICI cytotoxicity.
Main Results:
- TKI treatment in cohort A significantly altered CD3% and neutrophil counts.
- Patients responding well to ICIs (cohort B) showed increased lymphocyte counts, while non-responders showed decreased counts.
- In vitro assays demonstrated that TKIs could either antagonize or enhance ICI efficacy depending on the patient's tumor and immune cells.
Conclusions:
- This study provides initial evidence that TKIs can modulate blood immune cells, potentially influencing ICI response in NSCLC.
- The findings highlight the need for further validation of blood biomarkers and in vitro assays to predict treatment outcomes.
- Identifying how TKIs affect immune cell dynamics is critical for optimizing combination therapies in NSCLC.
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