PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer.

Autor:	Dosset M; INSERM, U1231, Dijon, France.; INSERM, U1098, Besançon, France.; LabEx LipSTIC, Besançon, France.; Université de Bourgogne Franche Comté, Dijon, France., Vargas TR; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Lagrange A; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Boidot R; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Centre Georges François Leclerc, Dijon, France., Végran F; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Centre Georges François Leclerc, Dijon, France., Roussey A; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Chalmin F; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Dondaine L; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Paul C; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Lauret Marie-Joseph E; INSERM, U1098, Besançon, France.; Université de Bourgogne Franche Comté, Dijon, France., Martin F; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France., Ryffel B; University of Cape Town, RSA, CNRS, UMR7355, Orleans, France, IDM., Borg C; INSERM, U1098, Besançon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Department of Medical Oncology, University Hospital of Besançon, France., Adotévi O; INSERM, U1098, Besançon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Department of Medical Oncology, University Hospital of Besançon, France., Ghiringhelli F; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Centre Georges François Leclerc, Dijon, France., Apetoh L; INSERM, U1231, Dijon, France.; Université de Bourgogne Franche Comté, Dijon, France.; Centre Georges François Leclerc, Dijon, France.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2018 Mar 15; Vol. 7 (6), pp. e1433981. Date of Electronic Publication: 2018 Mar 15 (Print Publication: 2018).
DOI:	10.1080/2162402X.2018.1433981
Abstrakt:	Background: 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.
Databáze:	MEDLINE
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