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.
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. giselle.boukhaled@uhnresearch.ca. (2) Princess Margaret Cancer Center, University Health N
Author Info: (1) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. giselle.boukhaled@uhnresearch.ca. (2) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (3) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (4) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (5) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (6) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (7) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. (8) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (9) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (10) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (11) Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. Department of Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA. (12) Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. (13) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (14) Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. (15) Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. (16) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (17) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. (18) Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. (19) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. (20) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. (21) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. (22) Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. (23) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (24) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. dbrooks@uhnresearch.ca. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. dbrooks@uhnresearch.ca.
