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

• Published in: EMBO reports Vol. 26; no. 2; pp. 521 - 559
• Main Authors: Shi, Yuhao, McKenery, Amber, Dolan, Melissa, Mastri, Michalis, Hill, James W, Dommer, Adam, Benzekry, Sebastien, Long, Mark, Abrams, Scott I, Puzanov, Igor, Ebos, John M L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2025; EMBO Press
• Subjects: Animals; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biomedical and Life Sciences; Cancer; Cell Line, Tumor; Drug Resistance, Neoplasm; EMBO03; EMBO19; EMBO37; Humans; Immune Checkpoint Inhibitors - pharmacology; Interferon Type I - metabolism; Life Sciences; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Signal Transduction - drug effects; Resistance; IFN; PD-L1; Immune-checkpoint; Secretome
• DOI: 10.1038/s44319-024-00333-0
• ISSN: 1469-3178; 1469-221X

Therapeutic inhibition of programmed cell death ligand (PD-L1) is linked to alterations in interferon (IFN) signaling. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined IFN-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 cytotoxicity, 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 highlighting 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. Synopsis Acquired resistance to PD-L1 inhibition can rewire the interferon-regulated secretory machinery in tumor cells, altering the immune microenvironment. These secretory programs may be exploited as biomarkers and therapeutic targets following treatment failure. Resistance to αPD-L1 treatment can increase type I IFN-regulated secretory programs. An αPD-L1 treatment-induced secretome (PTIS) can suppress CD8 T cell function and protect resistant tumor cells from splenocyte cytotoxicity. Blocking IFN signaling and the PTIS can slow resistant tumor growth. Acquired resistance to PD-L1 inhibition can rewire the interferon-regulated secretory machinery in tumor cells, altering the immune microenvironment. These secretory programs may be exploited as biomarkers and therapeutic targets following treatment failure.