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

  • Sarra Benkhelifa
  • Hayet Rafa
  • Said Belhadef
  • Hayat Ait-kaci
  • Oussama Medjeber
  • Mourad Belkhelfa
  • Sabah Hetit
  • Sonia Ait-Younes
  • Yvan De launoit
  • Olivier Moralès
  • Hassen Mahfouf
  • Nadira Delhem
  • Chafia Touil-BoukoffaEmail author
Original Article


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.


Colorectal Cancer iNOS/NO system Host immune responses Cetuximab and chemotherapy Immunomodulation 



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. 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. Special thanks are extended to Dr. Mohamed Boudjelal and Science Edit for the Developing World for editing the English Language of the paper.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest related to this article.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sarra Benkhelifa
    • 1
  • Hayet Rafa
    • 1
    • 2
  • Said Belhadef
    • 3
  • Hayat Ait-kaci
    • 4
  • Oussama Medjeber
    • 1
  • Mourad Belkhelfa
    • 1
  • Sabah Hetit
    • 5
  • Sonia Ait-Younes
    • 6
  • Yvan De launoit
    • 2
  • Olivier Moralès
    • 2
  • Hassen Mahfouf
    • 3
  • Nadira Delhem
    • 2
  • Chafia Touil-Boukoffa
    • 1
    Email author
  1. 1.Team Cytokines and NO Synthases-Immunity and Pathogenesis, Laboratory of Cellular and Molecular Biology (LBCM), Faculty of Biological ScienceUniversity of Sciences and Technology (USTHB)AlgiersAlgeria
  2. 2.Institut de Biologie de Lille, UMR 8161, CNRS, Institut Pasteur de Lille, University of LilleNord De LilleFrance
  3. 3.Oncology ServiceRouiba HospitalAlgiersAlgeria
  4. 4.Anatomical Pathology ServiceMustapha Pacha HospitalAlgiersAlgeria
  5. 5.Department of GastroenterologyIssad Hassani Hospital (Beni-Messous)AlgiersAlgeria
  6. 6.Anatomical Pathology ServiceNafissa Hamoud Hospital (Hussein-Dey)AlgiersAlgeria

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