PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer.
Fiche publication
Date publication
janvier 2018
Journal
Oncoimmunology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Dr BOIDOT Romain, Pr BORG Christophe, Pr GHIRINGHELLI François, Pr PAUL Catherine, Dr VEGRAN Frédérique, Dr CHALMIN Fanny
Tous les auteurs :
Dosset M, Vargas TR, Lagrange A, Boidot R, Végran F, Roussey A, Chalmin F, Dondaine L, Paul C, Marie-Joseph EL, Martin F, Ryffel B, Borg C, Adotévi O, Ghiringhelli F, Apetoh L
Lien Pubmed
Résumé
Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1 CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-γ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.
Mots clés
CD8 T cells, PD-1/PD-L1 pathway, chemotherapy, colorectal cancer, adaptive immune resistance, immunotherapy
Référence
Oncoimmunology. 2018 ;7(6):e1433981