Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients
Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with res...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1097117/full |
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| author | Shayista Akbar Afsheen Raza Afsheen Raza Reyad Mohsin Aladdin Kanbour Shahnaz Qadri Aijaz Parray Abdul Rehman Zar Gul Anite Philip Suma Vijayakumar Maysaloun Merhi Maysaloun Merhi Shereena Hydrose Shereena Hydrose Varghese Philipose Inchakalody Varghese Philipose Inchakalody Rajaa Al-Abdulla Wafa Abualainin Shaza Abu Sirriya Issam Al-Bozom Shahab Uddin Shahab Uddin Omar Muhammad Khan Mohamed Izham Mohamed Ibrahim Ussama Al Homsi Said Dermime Said Dermime Said Dermime |
| author_facet | Shayista Akbar Afsheen Raza Afsheen Raza Reyad Mohsin Aladdin Kanbour Shahnaz Qadri Aijaz Parray Abdul Rehman Zar Gul Anite Philip Suma Vijayakumar Maysaloun Merhi Maysaloun Merhi Shereena Hydrose Shereena Hydrose Varghese Philipose Inchakalody Varghese Philipose Inchakalody Rajaa Al-Abdulla Wafa Abualainin Shaza Abu Sirriya Issam Al-Bozom Shahab Uddin Shahab Uddin Omar Muhammad Khan Mohamed Izham Mohamed Ibrahim Ussama Al Homsi Said Dermime Said Dermime Said Dermime |
| author_sort | Shayista Akbar |
| collection | DOAJ |
| description | Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p<0.0001; Nectin-2, p<0.0001; NT5E, p<0.0001; Siglec-7, p<0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p<0.0001; MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients. |
| first_indexed | 2024-04-10T22:17:10Z |
| format | Article |
| id | doaj.art-207168b5e2c245d9b4aedca837e00d72 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T22:17:10Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-207168b5e2c245d9b4aedca837e00d722023-01-18T07:38:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011310.3389/fimmu.2022.10971171097117Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patientsShayista Akbar0Afsheen Raza1Afsheen Raza2Reyad Mohsin3Aladdin Kanbour4Shahnaz Qadri5Aijaz Parray6Abdul Rehman Zar Gul7Anite Philip8Suma Vijayakumar9Maysaloun Merhi10Maysaloun Merhi11Shereena Hydrose12Shereena Hydrose13Varghese Philipose Inchakalody14Varghese Philipose Inchakalody15Rajaa Al-Abdulla16Wafa Abualainin17Shaza Abu Sirriya18Issam Al-Bozom19Shahab Uddin20Shahab Uddin21Omar Muhammad Khan22Mohamed Izham Mohamed Ibrahim23Ussama Al Homsi24Said Dermime25Said Dermime26Said Dermime27College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarTranslational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarIrma Lerma Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, United StatesNeuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarTranslational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarTranslational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarTranslational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha, QatarAnatomical Pathology, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, QatarDiagnostic Genomic Division, Solid Tumor Section, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, QatarDiagnostic Genomic Division, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, QatarAnatomical Pathology, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, QatarTranslational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar0Laboratory Animal Research Center, Qatar University, Doha, QatarCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar1Clinical Pharmacy and Practice Department, College of Pharmacy, QU Health, Qatar University, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, QatarDepartment of Medical Oncology, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarTranslational Cancer Research Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha, QatarImmune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p<0.0001; Nectin-2, p<0.0001; NT5E, p<0.0001; Siglec-7, p<0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p<0.0001; MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1097117/fullexosomesNSCLCbiomarkersimmune-checkpoint inhibitorsimmune-oncological-checkpointscytokines |
| spellingShingle | Shayista Akbar Afsheen Raza Afsheen Raza Reyad Mohsin Aladdin Kanbour Shahnaz Qadri Aijaz Parray Abdul Rehman Zar Gul Anite Philip Suma Vijayakumar Maysaloun Merhi Maysaloun Merhi Shereena Hydrose Shereena Hydrose Varghese Philipose Inchakalody Varghese Philipose Inchakalody Rajaa Al-Abdulla Wafa Abualainin Shaza Abu Sirriya Issam Al-Bozom Shahab Uddin Shahab Uddin Omar Muhammad Khan Mohamed Izham Mohamed Ibrahim Ussama Al Homsi Said Dermime Said Dermime Said Dermime Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients Frontiers in Immunology exosomes NSCLC biomarkers immune-checkpoint inhibitors immune-oncological-checkpoints cytokines |
| title | Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients |
| title_full | Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients |
| title_fullStr | Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients |
| title_full_unstemmed | Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients |
| title_short | Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients |
| title_sort | circulating exosomal immuno oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti pd 1 pd l1 therapy in non small cell lung cancer patients |
| topic | exosomes NSCLC biomarkers immune-checkpoint inhibitors immune-oncological-checkpoints cytokines |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1097117/full |
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