GTN Enhances Antitumor Effects of Doxorubicin in TNBC by Targeting the Immunosuppressive Activity of PMN-MDSC.

Fiche publication

Date publication

juin 2023

Journal

Cancers

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BETTAIEB Ali , Dr BOIDOT Romain , Pr GHIRINGHELLI François , Dr HERMETET François , Pr PAUL Catherine , Mme TRUNTZER Caroline , Dr VEGRAN Frédérique , Dr BRUCHARD Mélanie , Dr DERANGERE Valentin

Tous les auteurs :
Mabrouk N, Racoeur C, Shan J, Massot A, Ghione S, Privat M, Dondaine L, Ballot E, Truntzer C, Boidot R, Hermetet F, Derangère V, Bruchard M, Végran F, Chouchane L, Ghiringhelli F, Bettaieb A, Paul C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/37370739

Résumé

(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8 lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.