Abstract
BackgroundLack 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).MethodsThe 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.ResultsExcept 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.ConclusionsTo 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.
Highlights
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)
To the best of our knowledge, this is the first study showing that tyrosine kinase inhibitors (TKIs) can have various effects on blood immune cells, which may affect their response to ICIs
Patients’ characteristics and baseline blood cell counts A total of 91 NSCLC patients were included in this study as illustrated in the flow chart (Fig. 1), 34 had blood samples after TKI treatment and 27 patients had pre-treatment blood samples, 35 had blood samples before and after ICI treatment, and 22 had blood samples collected at diagnosis only
Summary
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). Immune checkpoint inhibitors (ICIs) have revolutionized the diagnosis and treatment for patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC). ICIs have low or inferior clinical efficacy compared to chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-rearranged mNSCLC [1,2,3]. ICI treatment has been associated with increased incidence and severity of interstitial lung disease and immune-mediated adverse effects (including pneumonitis, colitis and hepatitis) when they are in sequential or concurrent use with small molecule tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant or ALKrearranged mNSCLC [5]. The updated report of PACIFIC [7] and retrospective analysis on durvalumab consolidation for patients with stage III NSCLC [8, 9] suggested that durvalumab might have limited clinical efficacy in the small subset of patients with EGFR- or HER2-mutant NSCLC
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