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Title: Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals
Authors: Zhou, Heng
Mondragón, Laura
Xie, Wei
Mauseth, Brynjar
Leduc, Marion
Sauvat, Allan
Silva, Lígia C. Gomes da 
Forveille, Sabrina
Iribarren, Kristina
Souquere, Sylvie
Bezu, Lucillia
Liu, Peng
Zhao, Liwei
Zitvogel, Laurence
Sveinbjørnsson, Baldur
Eksteen, J Johannes
Rekdal, Øystein
Kepp, Oliver
Kroemer, Guido
Issue Date: 23-Oct-2018
Publisher: Springer Nature
Project: H.Z. and P.L. were supported by the China Scholarship Council, L.Z. is supported by the Ligue contre le Cancer, G.K. and L.Z. are supported by the Ligue contre le Cancer (équipes labelisées); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); the Swiss Bridge Foundation, ISREC and the Paris Alliance of Cancer Research Institutes (PACRI). This project was supported by the Norwegian Research Council (254800, 257967). LCGdS is supported by Portuguese Science Foundation (ref. SFRH/BPD/93562/2013). 
Serial title, monograph or event: Cell Death and Disease
Volume: 9
Issue: 11
Abstract: Oncolytic peptides and peptidomimetics are being optimized for the treatment of cancer by selecting agents with high cytotoxic potential to kill a maximum of tumor cells as well as the capacity to trigger anticancer immune responses and hence to achieve long-term effects beyond therapeutic discontinuation. Here, we report on the characterization of two novel oncolytic peptides, DTT-205 and DTT-304 that both selectively enrich in the lysosomal compartment of cancer cells yet differ to some extent in their cytotoxic mode of action. While DTT-304 can trigger the aggregation of RIP3 in ripoptosomes, coupled to the phosphorylation of MLKL by RIP3, DTT-205 fails to activate RIP3. Accordingly, knockout of either RIP3 or MLKL caused partial resistance against cell killing by DTT-304 but not DTT-205. In contrast, both agents shared common features in other aspects of pro-death signaling in the sense that their cytotoxic effects were strongly inhibited by both serum and antioxidants, partially reduced by lysosomal inhibition with bafilomycin A1 or double knockout of Bax and Bak, yet totally refractory to caspase inhibition. Both DTT-304 and DTT-205 caused the exposure of calreticulin at the cell surface, as well as the release of HMGB1 from the cells. Mice bearing established subcutaneous cancers could be cured by local injection of DTT-205 or DTT-304, and this effect depended on T lymphocytes, as it led to the establishment of a long-term memory response against tumor-associated antigens. Thus, mice that had been cured from cancer by the administration of DTT compounds were refractory against rechallenge with the same cancer type several months after the disappearance of the primary lesion. In summary, DTT-205 and DTT-304 both have the capacity to induce immunotherapeutic oncolysis.
ISSN: 2041-4889
DOI: 10.1038/s41419-018-1127-3
Rights: openAccess
Appears in Collections:FCTUC Química - Artigos em Revistas Internacionais

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