Therapy-induced necroptosis renders autochthonous mammary tumors susceptible to checkpoint blockade immunotherapy Samuel T. Workenhe1*, David Bakhshinyan2, Jiarun Wei1, Kelly L. MacNeill1, Andrew Nguyen1, Dianrong Li3,Yonghong Wan1,Xiadong Wang3, Jonathan L. Bramson 1, Karen L. Mossman 1* 1McMaster Immunology Research Centre, Institute for Infectious Disease Research, Department of Pathology and Molecular Medicine, McMaster University, 2Stem Cell and Cancer Research Institute, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada, 3National Institute of Biological Sciences, Beijing, China *Correspondence: Samuel T. Workenhe - firstname.lastname@example.orgemail@example.com Karen L. Mossman - firstname.lastname@example.org
Immune checkpoint inhibitors show therapeutic effect in small fractions of patients that have a CD8+ T cell infiltrate. As a result, treatments that allow CD8+ T cell priming andinfiltration into the tumor are desirable for combination with checkpoint inhibitors. Using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether induction of immunogenic cell death overcomes failed spontaneous priming. By screening inducers of immunogenic cell death, we identified an immunogenic therapy, which activates necroptosis and induces T cell infiltration in both treated and distant tumors of two distinct autochthonous mammary tumor models. We show that pharmacological inhibition or genetic ablation of components of the necroptosis machinery abrogates therapeutic efficacy of immunogenic therapy, suggesting that the necroptosis is the source of immunogenicity. Moreover, our study provides evidence that therapy-induced necroptosis attracts immune cells into the tumor microenvironment, rendering tumor cells susceptible to checkpoint blockade immunotherapy.