Trifluridine/tipiracil plus oxaliplatin improves PD-1 blockade in colorectal cancer by inducing immunogenic cell death and depleting macrophages.
Fiche publication
Date publication
octobre 2019
Journal
Cancer immunology research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François, Dr LIMAGNE Emeric, Dr DERANGERE Valentin, Dr FUMET Jean-David, Dr THIBAUDIN Marion
Tous les auteurs :
Limagne E, Thibaudin M, Nuttin L, Spill A, Dérangère V, Fumet JD, Amellal N, Peranzoni E, Cattan V, Ghiringhelli F
Lien Pubmed
Résumé
Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, only the combination was able to induce ICD, but not the single agents, although all treatment groups showed T cell-dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSC), but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T cells infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti-PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti-PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in metastatic colorectal cancer patients.
Référence
Cancer Immunol Res. 2019 Oct 14;: