title: Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX-Bevacizumab Drug Treatment Regimen.
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.
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France. elimagne@cgfl.fr fghiringhelli@cgfl.fr.
authors: Emeric
authors: E
authors: Limagne
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France.
authors: Romain
authors: R
authors: Euvrard
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France.
authors: Marion
authors: M
authors: Thibaudin
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Cédric
authors: C
authors: Rébé
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Valentin
authors: V
authors: Derangère
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Angélique
authors: A
authors: Chevriaux
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Romain
authors: R
authors: Boidot
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Frédérique
authors: F
authors: Végran
authors: Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. INSERM U1194, Université de Montpellier, Montpellier, France. OREGA Biotech, Ecully, France.
authors: Nathalie
authors: N
authors: Bonnefoy
authors: Centre Georges François Leclerc, Dijon, France.
authors: Julie
authors: J
authors: Vincent
authors: Centre Georges François Leclerc, Dijon, France.
authors: Leila
authors: L
authors: Bengrine-Lefevre
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France.
authors: Sylvain
authors: S
authors: Ladoire
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France.
authors: Dominique
authors: D
authors: Delmas
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France.
authors: Lionel
authors: L
authors: Apetoh
authors: INSERM, U866, Dijon, France. UFR des Sciences de Santé, Université de Bourgogne-Franche Comté, Dijon, France. Centre Georges François Leclerc, Dijon, France. Plateforme de Transfert en Biologie Cancérologique, CGFL, Dijon, France. elimagne@cgfl.fr fghiringhelli@cgfl.fr.
authors: François
authors: F
authors: Ghiringhelli
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D018572:Disease-Free Survival; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil