American Association for Cancer Research
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Supplementary Figure 6: mRNA relative expression of genes involved in immunosuppression from Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX–Bevacizumab Drug Treatment Regimen

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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

gMDSC and mMDSC were cell sorted from four mCRC patient blood. mRNA were extracted and the expression of Entpd1, Nt5e, Pdl1, Pdl2, Indo, Arg1 and Inos was determined using RT-qPCR.

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

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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.

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