Small molecule tyrosine kinase inhibitors modulated blood immune cell counts in patients with oncogene-driven NSCLC

Abstract

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.

Hospitalized cancer patients with comorbidities and low lymphocyte counts had poor clinical outcomes to immune checkpoint inhibitors

“…Therefore, it is reasonable to hypothesize that a low pre-treatment ALC is associated with a poor response to ICI therapy. Our study confirms this finding in line with previous reports ( 36 , 37 ), showing pre-treatment ALC <600 cells/µL were associated with poor PFS (0.33 vs. 1.35 months; HR 6.9, 95% CI 10.8-25.9, p=0.0053) and poor OS (0.33 vs. 2.34 months; HR 4.66, 95% CI 1.2-17.5, p=0.0236) ( Figure 4 ). Furthermore, patients with ALC <600 cells/µL were less likely to receive a subsequent ICI dose than their counterparts (28.6% vs 36.4%).…”

“…In recent years, dNLR has been used as a novel biomarker to predict response to immunotherapy in various cancers including NSCLC, melanoma and head and neck cancers ( 39 , 40 ). It has been shown that a high pre-treatment dNLR (indicating a high inflammatory state) is associated with poor OS and PFS in a variety of cancers ( 37 , 39 – 42 ). For instance, Bongiovanni et al, observed a positive association between OS and a NLR ≤ 5 ( 42 ).…”

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer

“…Peripheral immune biomarkers in NSCLC present a multifaceted landscape, comprising many components that undergo alterations during natural tumor progression and therapeutic interventions. Our prior investigations have highlighted that anti-cancer agents, including small molecule tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs), exert modulatory effects on the immune milieu and peripheral blood immune cells of advanced NSCLC patients [137]. For instance, the emergence of post-treatment lymphopenia was discernibly linked with suboptimal clinical outcomes in this patient cohort [138].…”