Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy.

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. 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. 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. 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.

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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.

Déclaration de conflit d'intérêts

EJ, GL, BY, YE, IS, ND, MH, CL, YB, MY are employed by Oncohost. RL, AD, YS are consultants of Oncohost. NR and AAm are employed by Asklepios Kliniken GmbH and Asklepios Fachkliniken Muenchen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from OncoHost. The funder had the following involvement in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication.