P-248Cetuximab (anti-EGFR) in combination with chemotherapy has no effect on proinflammatory cytokines and markers of T regulatory cells in RAS wild type metastatic colorectal cancer: A study in Algerian patients

Introduction: Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. More than 30% patients present with metastases at diagnoses and will require systemic chemotherapy. The development of targeted therapies designed to inhibit or block key signaling pathways involved in tumor growth and dissemination to metastatic sites. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Anti-EGFR Cetuximab (chimeric IgG1 monoclonal antibody) binds epidermal growth factor (EGFR) and is used to treat RAS wild type metastatic colorectal cancer (mCCR); it is hypothesized that Cetuximab may have a beneficial effect on cancer survival by activating an anti-tumor immune response in cancer patients. Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. Despite the results achieved with targeted therapies, most mCRC patients will experience a disease relapse and the effect of these agents on immune response remains unclear. Methods: Forty-five Algerian patients with metastatic colorectal cancer (mCCR) treated with Cetuximab in combination with chemotherapy agents, 30 patients treated with chemotherapy alone, and 23 patients without treatment were enrolled in this study. We examined the effect of targeted therapy (anti-EGFR) and chemotherapy on Nitric oxide synthase2 (NOS2), proinflammatory cytokines production, and markers expression of T regulatory cells (Treg) in Algerian patients with metastatic colorectal cancer using transcriptomic analysis and ELISA assays. We also investigated the expression of CD4 and CD25 (markers of CD4+CD25+hight T regulatory cells) in peripheral blood mononuclear cells (PBMC) using flow cytometry analysis. Results: Our results pointed out that anti-EGFR has no effect on NO/NOS2 and proinflammatory cytokines (TNF-α, IL-17A, IL-6, IFN-γ) expression in vivo in comparison with patients without therapy (P > 0.05). We also showed that the combination of anti-EGFR and chemotherapy has no effect on Treg markers expression (CD4+CD25+hight Treg) in PBMC of mCRC patients (P > 0.05). In contrast, our results show that treatment with chemotherapy alone down-regulated the NO/NOS2, IL-17A, and TNF- α expression (P < 0.01), but has no effect on IFN-γ and Treg markers expression (P > 0.05). Conclusion: We conclude that the targeted therapy with anti-EGFR in combination with chemotherapy has no effect on inflammatory mediator’s production (Nitric oxide and proinflammatory cytokines), as well as the phenotypic and fonctionnel markers of T regulatory cells in RAS wild type metastatic colorectal cancer. It seems that the treatment of different forms of CCR included RAS wild type mCRC requires new strategies to improve the current therapy