Article Dans Une Revue EMBO Reports Année : 2024

Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors

Résumé

Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. SinceIFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examinedIFN-related secretory changes in tumor cells following resistance to PD-L1 inhibition. Here we report an anti-PD-L1 treatment-induced secretome (PTIS) in tumor models of acquired resistance that is regulated by type I IFNs. These secretory changes can suppress activation of T cells ex vivo while diminishing tumor cell cytotoxcity, revealing that tumor-intrinsic treatment adaptations can exert broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth can slow or stop when PTIS components are disrupted individually, or when type I IFN signaling machinery is blocked. Interestingly, genetic and therapeutic disruption of PD-L1 in vitro can only partially recapitulate the PTIS phenotype high-lighting the importance of developing in vivo-based resistance models to more faithfully mimic clinically-relevant treatment failure. Together, this study shows acquired resistance to immune-checkpoint inhibitors ‘rewires’ tumor secretory programs controlled by type I IFNs that, in turn, can protect from immune cell attack.

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hal-04387866 , version 1 (11-01-2024)
hal-04387866 , version 2 (13-01-2025)

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Yuhao Shi, Amber Mckenery, Melissa Dolan, Michalis Mastri, James W Hill, et al.. Acquired resistance to PD-L1 inhibition enhances a type I IFN-regulated secretory program in tumors. EMBO Reports, 2024, 26, pp.521 - 559. ⟨10.1038/s44319-024-00333-0⟩. ⟨hal-04387866v2⟩
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