De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors

• Published in: Communications biology Vol. 3; no. 1; p. 645
• Main Authors: Workenhe, Samuel T., Nguyen, Andrew, Bakhshinyan, David, Wei, Jiarun, Hare, David N., MacNeill, Kelly L., Wan, Yonghong, Oberst, Andrew, Bramson, Jonathan L., Nasir, Jalees A., Vito, Alyssa, El-Sayes, Nader, Singh, Sheila K., McArthur, Andrew G., Mossman, Karen L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.11.2020; Nature Publishing Group
• Subjects: 631/250/1933; 631/250/2152/1566/20; 631/67/1059; 692/67; Animals; Antineoplastic Agents; Biology; Biomedical and Life Sciences; Breast cancer; Cancer immunotherapy; Cell Line, Tumor; Chemotherapy; Cytokines; Cytotoxicity; Female; Gene Deletion; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy; Inflammation; Inflammation - metabolism; Life Sciences; Lung cancer; Lymphocytes; Lymphocytes T; Mammary Neoplasms, Animal; Melanoma; Mice; Mice, Transgenic; Mitomycin C; Monoclonal antibodies; Myeloid cells; Necroptosis; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses; Osteosarcoma - metabolism; Tumor Microenvironment; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01362-w

Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors. Workenhe et al. show in mice that a combination of oncolytic HSV-1 virus and Mitomycin-C activates an inflammatory response, through necroptosis induction, that renders tumours susceptible to immune checkpoint inhibitors. These findings informs on the potential role of necroptosis in immunotherapy approaches.