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

Magalie Dosset 1, 2, 3, 4 Thaiz Rivera Vargas 2, 4 Anais Lagrange 2, 4 Romain Boidot 2, 4, 5 Frédérique Vegran 2, 4, 5 Aurélie Roussey 2, 4 Fanny Chalmin 2, 4 Lucile Dondaine 2, 4 Catherine Paul 4, 2 Elodie Lauret Marie-Joseph 4, 2 François Martin 2, 4 Bernhard Ryffel 6, 7 Christophe Borg 1, 4, 8 Olivier Adotévi 1, 4, 8 François Ghiringhelli 2, 4, 5 Lionel Apetoh 5, 4, 2, *
* Auteur correspondant
1 HOTE GREFFON - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
2 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
3 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
4 UBFC - Université Bourgogne Franche-Comté [COMUE]
5 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
6 University of Cape Town
7 INEM - Immunologie et Neurogénétique Expérimentales et Moléculaires
8 Service d'Oncologie Médicale [CHRU Besançon]
Abstract : 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.
Keywords : CD8 T cells chemotherapy colorectal cancer adaptive immune resistance PD-1/PD-L1 pathway immunotherapy
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01928503
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mardi 20 novembre 2018 - 15:37:29
Dernière modification le : vendredi 18 septembre 2020 - 14:34:59

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UNIV-BOURGOGNE | LNC-CD4DNA | LNC-CADIR | CNRS | UNIV-FCOMTE | INRA | CGFL | EPHE | FNCLCC | UMR645 | LNC-UMR866 | UNIV-ORLEANS | UNIV-PARIS-SACLAY | UNIV-MONTPELLIER | INRAE | PSL

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Magalie Dosset, Thaiz Rivera Vargas, Anais Lagrange, Romain Boidot, Frédérique Vegran, et al.. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. OncoImmunology, Taylor & Francis, 2018, 7 (6), pp.e1433981. ⟨10.1080/2162402X.2018.1433981⟩. ⟨hal-01928503⟩

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