journal contribution
posted on 2023-03-31, 00:27 authored by Emeric Limagne, Romain Euvrard, Marion Thibaudin, Cédric Rébé, Valentin Derangère, Angélique Chevriaux, Romain Boidot, Frédérique Végran, Nathalie Bonnefoy, Julie Vincent, Leila Bengrine-Lefevre, Sylvain Ladoire, Dominique Delmas, Lionel Apetoh, François Ghiringhelli PBMCs of mCRC patients were stained after PMA/ionomycin/Brefeldin/Monensin stimulation (4 hrs) with anti-CD4, anti-CD45RA, anti-CCR6, anti-CXCR3, anti-IFN-γ and anti-IL-17A antibodies and analyzed by flow cytometry. The expression of IFN-γ and/or IL-17A on memory CD4 (CD45RA- CD4+) Th1 (CCR6- CXCR3+), Th17 (CCR6+ CXCR3-), Th17/Th1 (CCR6+ CXCR3+) and CCR6- CXCR3- cells is depicted.
Funding
Ligue Nationale contre le Cancer
Institut National Du Cancer
Association pour la Recherche sur le Cancer
the Conseil Régional Bourgogne
Inserm
Fondation pour la Recherche Médicale
Fondation de France
Fondation Lilliane Betancourt
French National Research Agency
Ligue Régionale contre le Cancer Comité Grand-Est
the Canceropôle Grand-Est
the European Community
Université de Montpellier
LabEx
History
ARTICLE ABSTRACT
Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX–bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX–bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX–bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241–52. ©2016 AACR.
