STING‐ATF3/type I interferon crosstalk: A potential target to improve anti‐tumour immunity in chemotherapy‐treated urothelial carcinoma

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Fauvre, Alexandra | Machu, Margot | Merienne, Audrey | Vezzio-Vie, Nadia | Bessede, Thomas | Robin, Mathilde | Garambois, Veronique | Taffoni, Clara | Laguette, Nadine | Gervois-Segain, Nadine | Jarry, Anne | Labarrière, Nathalie | Allory, Yves | Larbouret, Christel | Gros, Laurent | Tosi, Diego | Solit, David B. | Pourquier, Philippe | Houédé, Nadine | Gongora, Celine

Edité par CCSD ; Heidelberg : Springer-Verlag -

International audience. Upper Tract Urothelial Carcinomas (UTUC) are extremely aggressive and immunosuppressed tumors of the ureter or renal pelvis with a high relapse rate (>50%). Here, we assessed the mechanism of action of chemotherapy combinations (platinum salts and gemcitabine) in 2D and 3D UTUC cell cultures, including heterotypic spheroids. The tested combinations induced immunogenic cell death associated with the activation of DNA damage pathways and STING signaling, but not type I interferon (IFN-I). We identified the ATF3 transcription factor as an inhibitor of inflammatory responses and IFN-I induction in UTUC, which hindered CD8+ T-cell infiltration and activation. Our data suggest that the tested combination of chemotherapy with ATF3 suppression/IFN-I may improve UTUC immunogenicity and therapeutic response.

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