Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy.

Abstract

Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 (-/-) and Mlkl (-/-) tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 (-/-) and Mlkl (-/-) cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

• Authors: Heng Yang, Yuting Ma, Guo Chen, Heng Zhou, Takahiro Yamazaki, Christophe Klein, Federico Pietrocola, Erika Vacchelli, Sylvie Souquere, Allan Sauvat, Laurence Zitvogel, Oliver Kepp, Guido Kroemer
• Journal: Oncoimmunology (Oncoimmunology) Vol. 5 Issue 6 Pg. e1149673 (Jun 2016) ISSN: 2162-4011 [Print] United States
• PMID: 27471616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)