Biological Insights From Plasma Proteomics of Non-small Cell Lung Cancer Patients Treated With Immunotherapy

Authors

Jair Bar
Raya Leibowitz
Niels Reinmuth
Astrid Ammendola
Eyal Jacob
Mor Moskovitz
Adva Levy-Barda
Michal Lotem
Rivka Katsenelson
Abed Agbarya
Mahmoud Abu-Amna
Maya Gottfried
Tatiana Harkovsky
Ido Wolf
Ella Tepper
Gil Loewenthal
Ben Yellin
Yehuda Brody
Nili Dahan
Maya Yanko
Coren Lahav
Michal Harel
Shani Raveh Shoval
Yehonatan Elon
Itamar Sela
Adam Dicker, Thomas Jefferson UniversityFollow
Yuval Shaked

Document Type

Article

Publication Date

2-29-2024

Comments

This article, first published by Frontiers Media, is the author's final published version in Frontiers in Immunology, Volume 15, 2024, Article number 1364473.

The published version is available at https://doi.org/10.3389/fimmu.2024.1364473.

Copyright © 2024 Bar, Leibowitz, Reinmuth, Ammendola, Jacob, Moskovitz, Levy-Barda, Lotem, Katsenelson, Agbarya, Abu-Amna, Gottfried, Harkovsky, Wolf, Tepper, Loewenthal, Yellin, Brody, Dahan, Yanko, Lahav, Harel, Raveh Shoval, Elon, Sela, Dicker and Shaked

Abstract

INTRODUCTION: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.

METHODS: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes.

RESULTS: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage.

CONCLUSIONS: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.

Recommended Citation

Bar, Jair; Leibowitz, Raya; Reinmuth, Niels; Ammendola, Astrid; Jacob, Eyal; Moskovitz, Mor; Levy-Barda, Adva; Lotem, Michal; Katsenelson, Rivka; Agbarya, Abed; Abu-Amna, Mahmoud; Gottfried, Maya; Harkovsky, Tatiana; Wolf, Ido; Tepper, Ella; Loewenthal, Gil; Yellin, Ben; Brody, Yehuda; Dahan, Nili; Yanko, Maya; Lahav, Coren; Harel, Michal; Raveh Shoval, Shani; Elon, Yehonatan; Sela, Itamar; Dicker, Adam; and Shaked, Yuval, "Biological Insights From Plasma Proteomics of Non-small Cell Lung Cancer Patients Treated With Immunotherapy" (2024). Department of Radiation Oncology Faculty Papers. Paper 189.
https://jdc.jefferson.edu/radoncfp/189

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

38487531

Language

English