Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression

Afsheen Raza; Reyad Mohsen; Aladdin Kanbour; Abdul Rehman Zar Gul; Anite Philip; Suma Vijayakumar; Shereena Hydrose; Kirti S Prabhu; Aisha Khamis Al-Suwaidi; Varghese Philipose Inchakalody; Maysaloun Merhi; Dina M Abo El-Ella; Melissa Annrose Tauro; Shayista Akbar; Issam Al-Bozom; Wafa Abualainin; Rajaa Al-Abdulla; Shaza Abu Sirriya; Suparna Hassnad; Shahab Uddin; Mohamed Izham Mohamed Ibrahim; Ussama Al Homsi; Said Demime

doi:10.3389/fimmu.2023.1157100

Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression

Front Immunol. 2023 May 15:14:1157100. doi: 10.3389/fimmu.2023.1157100. eCollection 2023.

Authors

Afsheen Raza^{1

2}, Reyad Mohsen¹, Aladdin Kanbour¹, Abdul Rehman Zar Gul¹, Anite Philip¹, Suma Vijayakumar¹, Shereena Hydrose^{1

2}, Kirti S Prabhu³, Aisha Khamis Al-Suwaidi^{1

2}, Varghese Philipose Inchakalody^{1

2}, Maysaloun Merhi^{1

2}, Dina M Abo El-Ella^{1

2}, Melissa Annrose Tauro⁴, Shayista Akbar⁵, Issam Al-Bozom⁶, Wafa Abualainin⁷, Rajaa Al-Abdulla⁶, Shaza Abu Sirriya⁷, Suparna Hassnad⁸, Shahab Uddin^{9

10}, Mohamed Izham Mohamed Ibrahim¹¹, Ussama Al Homsi¹, Said Demime^{1

2

5}

Affiliations

¹ Department of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
² Translational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
³ Translational Research Institute (TRI), Academic Health System, Hamad Medical Corporation, Doha, Qatar.
⁴ Department of Human Genetics, Sidra Medical and Research Center, Doha, Qatar.
⁵ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁶ Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar.
⁷ Diagnostic Genomic Division , Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar.
⁸ Department of Radiation Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
⁹ Translational Research Institute and Dermatology Institute, Academic Health System, Hamad, Medical Corporation, Doha, Qatar.
¹⁰ Laboratory Animal Research Center, Qatar University, Doha, Qatar.
¹¹ Clinical Pharmacy and Practice Department, College of Pharmacy, Qatar University (QU) Health, Qatar University, Doha, Qatar.

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.

Keywords: CEA; anti-PD-1; anti-PD-L1; non-small cell lung cancer; predictive soluble biomarkers; tissue PD-L1.

Copyright © 2023 Raza, Mohsen, Kanbour, Zar Gul, Philip, Vijayakumar, Hydrose, Prabhu, Al-Suwaidi, Inchakalody, Merhi, Abo El-Ella, Tauro, Akbar, Al-Bozom, Abualainin, Al-Abdulla, Sirriya, Hassnad, Uddin, Mohamed Ibrahim, Al Homsi and Demime.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Immunological* / pharmacology
Carcinoma, Non-Small-Cell Lung* / pathology
Humans
Immunologic Factors / therapeutic use
Lung Neoplasms* / pathology
Progression-Free Survival
Treatment Outcome

Substances

Antineoplastic Agents, Immunological
Immunologic Factors

Grants and funding

This research was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar, grant number MRC-01-20-507 and the Article Processing Charges was funded by Academic Health System, Medical Research Center, Hamad Medical Corporation, Doha, Qatar. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.