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Peer-reviewedCC BY 4.0Frontiers in Immunology

Cardiovascular biomarker phenotype associated with immune checkpoint inhibitor therapy in patients with non-small cell lung cancer: an exploratory blood transcriptome study

  • Joanna Ziemska-Legięcka1,2
  • Natalia Żeber-Lubecka1,2
  • Magdalena Borucka3
  • Dorota Kaczmarska4
  • Magdalena Zaborowska-Szmit3
  • Patrycja Ozdowska4
  • Katarzyna Zajda3
  • Anna Janowicz-Żebrowska3
  • Michalina Dąbrowska1
  • Lukasz Serementa5
  • Tadeusz M. Orlowski5
  • Maciej Krzakowski3
4 more authors
  • Sebastian Szmit4,6
  • Michał Mikula1
  • Jerzy Ostrowski1
  • Beata Jagielska7
7 affiliations
  1. 1Department of Experimental Oncology, Laboratory of Cancer Metabolism, Maria Sklodowska-Curie National Research Institute of Oncology
  2. 2Department of Gastroenterology, Hepatology and Clinical Oncology, Center of Postgraduate Medical Education
  3. 3Department of Lung Cancer and Thoracic Tumours, Maria Skłodowska-Curie National Research Institute of Oncology
  4. 4Cardio-Oncology Unit, Maria Skłodowska-Curie National Research Institute of Oncology
  5. 5Department of Surgery, Department of Thoracic Surgery, National Research Institute of Chest Diseases
  6. 6Department of Cardio-Oncology, Centre of Postgraduate Medical Education
  7. 7Maria Skłodowska-Curie National Research Institute of Oncology
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Abstract

Background: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced non-small cell lung cancer (NSCLC), but their use is associated with potentially serious immune-related cardiotoxicity, often reflected by elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Identifying patients at risk before treatment initiation remains a major clinical challenge. The aim of this study was to investigate whether peripheral blood transcriptomic profiles are associated with susceptibility to an ICI-related cardiac biomarker-defined phenotype.

Methods: Peripheral blood RNA sequencing was performed in patients with advanced NSCLC receiving anti-PD-1/PD-L1 therapy (n=61) and in a control group with predominantly early-stage disease (n=29). Differential expression and functional enrichment analyses were used to characterize global and baseline transcriptomic differences, early treatment-related changes, and molecular signatures associated with NT-proBNP elevation and survival.

Results: Despite substantial transcriptomic overlap (86.0% of genes shared), global analysis revealed significant differences between early- and advanced-stage disease, as demonstrated by PCA and PERMANOVA. Baseline comparison in patients who subsequently developed NT-proBNP elevation identified a small set of differentially expressed genes (n=9), indicating subtle pre-treatment differences in regulatory and signaling pathways. Early response analysis demonstrated modest transcriptional changes after the first ICI cycle, with enrichment analyses pointing to immune-related pathways, including leukocyte migration and cytokine signaling. NT-proBNP-defined phenotype was associated with exploratory differential gene expression patterns and enrichment of pathways related to T-cell activation and immune signaling. Exploratory survival-associated transcriptomic profiles were characterized by enrichment of pathways related to platelet activation, coagulation and cell adhesion.

Conclusion: Peripheral blood transcriptomic profiling reveals stage-dependent and clinically relevant transcriptomic patterns in NSCLC, including early immune-related transcriptional changes and signatures associated with a cardiovascular biomarker phenotype defined by NT-proBNP changes. Although these alterations are subtle, they highlight the potential of peripheral blood transcriptomic profiling to identify transcriptomic signatures associated with an NT-proBNP-defined cardiovascular biomarker phenotype. Given the exploratory nature of the analyses and the relatively small size of several subgroups, particularly the survival comparison, these findings should be interpreted as hypothesis-generating and require validation in independent cohorts.

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Cite

BibTeXRIS
BibTeX
@article{ziemskalegiecka2026cardiovascular,
  title = {{Cardiovascular biomarker phenotype associated with immune checkpoint inhibitor therapy in patients with non-small cell lung cancer: an exploratory blood transcriptome study}},
  author = {Joanna Ziemska-Legięcka and Natalia Żeber-Lubecka and Magdalena Borucka and Dorota Kaczmarska and Magdalena Zaborowska-Szmit and Patrycja Ozdowska and Katarzyna Zajda and Anna Janowicz-Żebrowska and Michalina Dąbrowska and Lukasz Serementa and Tadeusz M. Orlowski and Maciej Krzakowski and Sebastian Szmit and Michał Mikula and Jerzy Ostrowski and Beata Jagielska},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1972440},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972440/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cardiovascular biomarker phenotype associated with immune checkpoint inhibitor therapy in patients with non-small cell lung cancer: an exploratory blood transcriptome study
AU  - Joanna Ziemska-Legięcka
AU  - Natalia Żeber-Lubecka
AU  - Magdalena Borucka
AU  - Dorota Kaczmarska
AU  - Magdalena Zaborowska-Szmit
AU  - Patrycja Ozdowska
AU  - Katarzyna Zajda
AU  - Anna Janowicz-Żebrowska
AU  - Michalina Dąbrowska
AU  - Lukasz Serementa
AU  - Tadeusz M. Orlowski
AU  - Maciej Krzakowski
AU  - Sebastian Szmit
AU  - Michał Mikula
AU  - Jerzy Ostrowski
AU  - Beata Jagielska
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1972440
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972440/full
AB  - Background: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced non-small cell lung cancer (NSCLC), but their use is associated with potentially serious immune-related cardiotoxicity, often reflected by elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Identifying patients at risk before treatment initiation remains a major clinical challenge. The aim of this study was to investigate whether peripheral blood transcriptomic profiles are associated with susceptibility to an ICI-related cardiac biomarker-defined phenotype.  Methods: Peripheral blood RNA sequencing was performed in patients with advanced NSCLC receiving anti-PD-1/PD-L1 therapy (n=61) and in a control group with predominantly early-stage disease (n=29). Differential expression and functional enrichment analyses were used to characterize global and baseline transcriptomic differences, early treatment-related changes, and molecular signatures associated with NT-proBNP elevation and survival.  Results: Despite substantial transcriptomic overlap (86.0% of genes shared), global analysis revealed significant differences between early- and advanced-stage disease, as demonstrated by PCA and PERMANOVA. Baseline comparison in patients who subsequently developed NT-proBNP elevation identified a small set of differentially expressed genes (n=9), indicating subtle pre-treatment differences in regulatory and signaling pathways. Early response analysis demonstrated modest transcriptional changes after the first ICI cycle, with enrichment analyses pointing to immune-related pathways, including leukocyte migration and cytokine signaling. NT-proBNP-defined phenotype was associated with exploratory differential gene expression patterns and enrichment of pathways related to T-cell activation and immune signaling. Exploratory survival-associated transcriptomic profiles were characterized by enrichment of pathways related to platelet activation, coagulation and cell adhesion.  Conclusion: Peripheral blood transcriptomic profiling reveals stage-dependent and clinically relevant transcriptomic patterns in NSCLC, including early immune-related transcriptional changes and signatures associated with a cardiovascular biomarker phenotype defined by NT-proBNP changes. Although these alterations are subtle, they highlight the potential of peripheral blood transcriptomic profiling to identify transcriptomic signatures associated with an NT-proBNP-defined cardiovascular biomarker phenotype. Given the exploratory nature of the analyses and the relatively small size of several subgroups, particularly the survival comparison, these findings should be interpreted as hypothesis-generating and require validation in independent cohorts.
SN  - 1664-3224
ER  -