Boukhaled et al. used mass cytometry and multi-omics analysis to establish physiological cell states of response to IFN-I that can predict outcomes of anti-PD-1 therapy. Patients with pre-therapy hyporesponsiveness to IFN-Is among their peripheral blood CD4+ and CD8+ effector T cells show improved responses to anti-PD-1 therapy and longer OS, whereas hyperresponsiveness to IFN-I was associated with treatment failure. IFN-I responsiveness was not associated with differences in tumor inflammation or mediated by IFN-I-stimulated genes (ISGs), but was associated with distinct gene expression and pre-existing chromatin accessibility for transcription factors at the basal state.
Contributed by Shishir Pant
ABSTRACT: Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.