1. Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy
- Author
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Sonia Ait-Younes, Mourad Belkhelfa, Chafia Touil-Boukoffa, Yvan de Launoit, Hassen Mahfouf, Hayet Rafa, Nadira Delhem, Hayat Ait-Kaci, Olivier Moralès, Sabah Hetit, Oussama Medjeber, Sarra Benkhelifa, Said Belhadef, Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), FGMGP/USTHB, Université d'Algérie, Hôpital Rouïba [Algerie], Le centre hospitalier universitaire (CHU) Mustapha Pacha [Alger], Centre Hospitalo-Universitaire de Béni-Messous, CHU Nafissa Hamoud [Hussein Dey], University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, They also thank the national agency of research development in health (ATRSS) which supported their project (code project: 03/06/01/10/011). They have also received support from the SIRIC ONCO Lille., The authors would like to gratefully thank all the participants involved in this study as well as the technical staff of the department of oncology (Rouiba Hospital) and Anatomic Pathology Service (Mustapha Pacha Hospital). They greatly thank Meroua BOUCHEMAL, Arezki CHEKAOUI and Dr. Kahina TOURI (USTHB, Algiers, Algeria) for all help and support of this work. Special thanks are extended to Dr. Mohamed Boudjelal and Science Edit for the Developing World for editing the English Language of the paper., Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,MESH: Up-Regulation/physiology ,MESH: Down-Regulation/drug effects ,MESH: Aged, 80 and over ,0302 clinical medicine ,Host immune responses ,MESH: Nitric Oxide/metabolism ,MESH: Colorectal Neoplasms/metabolism ,Pharmacology (medical) ,ComputingMilieux_MISCELLANEOUS ,MESH: Aged ,MESH: Middle Aged ,Cetuximab ,MESH: Nitric Oxide Synthase Type II/metabolism ,FOXP3 ,3. Good health ,medicine.anatomical_structure ,MESH: Cetuximab/therapeutic use ,iNOS/NO system ,MESH: Up-Regulation/drug effects ,medicine.symptom ,medicine.drug ,Immunology ,Inflammation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH: Immunologic Factors/metabolism ,Peripheral blood mononuclear cell ,Immunomodulation ,03 medical and health sciences ,Immune system ,MESH: Down-Regulation/physiology ,medicine ,MESH: Biomarkers, Tumor/metabolism ,Cetuximab and chemotherapy ,Colorectal Cancer ,Pharmacology ,Chemotherapy ,MESH: Humans ,business.industry ,MESH: Adult ,medicine.disease ,MESH: Male ,030104 developmental biology ,Cancer research ,MESH: Colorectal Neoplasms/drug therapy ,business ,MESH: Female ,Memory T cell ,MESH: T-Lymphocytes, Regulatory/drug effects ,030217 neurology & neurosurgery ,MESH: Forkhead Transcription Factors/metabolism - Abstract
International audience; Colorectal cancer (CRC) remains the most cancer type related to chronic inflammation; however, the mechanisms that link inflammation to CRC development and progression are still poorly understood. Our study aimed to investigate one of the prominent inflammatory response in cancers, iNOS/NO system. In this regard, we evaluated the link between the iNOS/NO system and CRC progression, its relation with the host immune responses and its response to cetuximab combined with chemotherapy. We found that the nitrite levels were nearly twice as high in metastatic CRC plasma and culture supernatants from PBMCs and tumor explants compared with those without metastases and healthy controls. Interestingly, we showed that the highest iNOS expression and NO levels are present in the damaged CRC tissues that have highest leukocyte infiltration. Our findings highlight the implication of iNOS/NO system in tissue alteration and leukocyte invasion. Thus, we observed imbalance between effector/memory T cell markers and Treg transcription factor (Foxp3). Accordingly, we detected higher IFNγ and T-bet expression levels in colorectal tumor tissues at early stage. In contrast, consistent with iNOS and Foxp3 expression, TGFβ, CTLA-4 and IL-10 were significantly related to the tumor stage progression. Furthermore, our study revealed that Cetuximab combined with chemotherapy treatment markedly down-regulates iNOS/NO system as well as IL-10 and TGFβ levels. Altogether, we conclude that cetuximab can potentiate the efficacy of chemotherapy, particularly by iNOS/NO system and immunosuppressive cytokines modulation. Thus, we suggest that iNOS/NO system may represent an attractive candidate biomarker for monitoring CRC progression, malignity and response to therapy.
- Published
- 2019
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