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RIPK1‐mediated immunogenic cell death promotes anti‐tumour immunity against soft‐tissue sarcoma

Henry G Smith, Kunzah Jamal, Jasbani Hs Dayal, Tencho Tenev, Joan Kyula‐Currie, Naomi Guppy, Patrycja Gazinska, Victoria Roulstone, Gianmaria Liccardi, Emma Davies, Ioannis Roxanis, Alan A Melcher, Andrew J Hayes, Gareth J Inman, Kevin J. Harrington , Pascal Meier
Published: 18 May 2020
 by  EMBO
EMBO Molecular Medicine , Volume 12; doi:10.15252/emmm.201910979

Abstract: Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti-tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term "immunogenic cell death" is not fully defined, activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre-clinical application of an in vivo treatment protocol for soft-tissue sarcoma that directly engages RIPK1-mediated immunogenic cell death. We find that RIPK1-mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1-induced cell death in patients with advanced disease at limb extremities.
Keywords: apoptosis / TNF / Soft-tissue Sarcoma / RIPK1 / Smac mimetics

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