Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals
Permanent lenke
https://hdl.handle.net/10037/15169Dato
2018-10-23Type
Journal articleTidsskriftartikkel
Peer reviewed
Forfatter
Zhou, Heng; Mondragón, Laura; Xie, Wei; Mauseth, Brynjar; Leduc, Marion; Sauvat, Allan; Gomes-da-Silva, Lígia C.; Forveille, Sabrina; Iribarren, Kristina; Souquere, Sylvie; Bezu, Lucillia; Liu, Peng; Zhao, Liwei; Zitvogel, Laurence; Sveinbjørnsson, Baldur; Eksteen, Jacobus Johannes; Rekdal, Øystein; Kepp, Oliver; Kroemer, GuidoSammendrag
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