Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals

• Published in: Cell death & disease 2018-10, Vol.9 (11), p.1086-14, Article 1086
• Main Authors: 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, J. Johannes, Rekdal, Øystein, Kepp, Oliver, Kroemer, Guido
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/56; 14/19; 14/28; 14/35; 38/77; 64/60; Animals; Antibodies; Antigen (tumor-associated); Antigens, Neoplasm - metabolism; Antioxidants; Apoptosis - drug effects; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; Biochemistry; Biomedical and Life Sciences; Calreticulin; Cancer; Caspase; Caspase 3 - metabolism; Cell Biology; Cell Culture; Cell surface; Cytotoxicity; Dithiothreitol; Drug Discovery - methods; Female; HMGB1 protein; HMGB1 Protein - metabolism; HT29 Cells; Humans; Immune response; Immunologic Memory - drug effects; Immunological memory; Immunology; Life Sciences; Lipid Droplets - drug effects; Long term memory; Long-term effects; Lymphocytes T; Lysosomes - drug effects; Medical disciplines: 700; Medicin och hälsovetenskap; Medisinske Fag: 700; Mice; Mice, Inbred C57BL; Necrosis; Neoplasms - drug therapy; Neoplasms - pathology; Oncolysis; Peptides; Peptides - chemical synthesis; Peptides - pharmacology; Peptides - therapeutic use; Peptidomimetics; Phosphorylation; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Treatment Outcome; Tumor cells; VDP
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1127-3

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.