In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional Predictor for Response to Immune Checkpoint Inhibition in NSCLC
(2025) In Journal of Thoracic Oncology- Abstract
Introduction: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. Methods: We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from... (More)
Introduction: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. Methods: We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms. Results: In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1). Conclusion: Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.
(Less)
- author
- Lindberg, Amanda
; Muhl, Lars
; Yu, Hui
; Hellberg, Louise
; Artursson, Rebecca
; Friedrich, Jakob
; Backman, Max
; Hekmati, Neda
; Mattsson, Johanna
; Lindskog, Cecilia
; Brunnström, Hans
LU
; Botling, Johan
; Mezheyeuski, Artur
; Broström, Erika
; Gulyas, Miklos
; Kärre, Klas
; Isaksson, Johan
; Micke, Patrick
and Strell, Carina
(Less) - organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- epub
- subject
- keywords
- Immune checkpoint inhibitor, non–small cell lung cancer, Programmed cell death protein 1, Programmed death ligand 1, Proximity ligation assay
- in
- Journal of Thoracic Oncology
- publisher
- Elsevier
- external identifiers
-
- pmid:39743139
- scopus:85216903906
- ISSN
- 1556-0864
- DOI
- 10.1016/j.jtho.2024.12.026
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 International Association for the Study of Lung Cancer
- id
- b64ef1cb-b568-49c0-9ffc-aed468612d1e
- date added to LUP
- 2025-04-22 11:08:57
- date last changed
- 2025-07-01 23:40:06
@article{b64ef1cb-b568-49c0-9ffc-aed468612d1e,
abstract = {{<p>Introduction: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. Methods: We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms. Results: In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1). Conclusion: Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.</p>}},
author = {{Lindberg, Amanda and Muhl, Lars and Yu, Hui and Hellberg, Louise and Artursson, Rebecca and Friedrich, Jakob and Backman, Max and Hekmati, Neda and Mattsson, Johanna and Lindskog, Cecilia and Brunnström, Hans and Botling, Johan and Mezheyeuski, Artur and Broström, Erika and Gulyas, Miklos and Kärre, Klas and Isaksson, Johan and Micke, Patrick and Strell, Carina}},
issn = {{1556-0864}},
keywords = {{Immune checkpoint inhibitor; non–small cell lung cancer; Programmed cell death protein 1; Programmed death ligand 1; Proximity ligation assay}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Journal of Thoracic Oncology}},
title = {{In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional Predictor for Response to Immune Checkpoint Inhibition in NSCLC}},
url = {{http://dx.doi.org/10.1016/j.jtho.2024.12.026}},
doi = {{10.1016/j.jtho.2024.12.026}},
year = {{2025}},
}