Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade

• DOI: 10.1136/jitc-2022-006602
• Publication Date: 2024-04-24T09:45:13Z
• Authors: Jason K Cullen; Pei-Yi Yap; Blake Ferguson; Zara C Bruce; Motoko Koyama; Herlina Handoko; Kevin Hendrawan; Jacinta L Simmons; Kelly M Brooks; Jenny Johns; Emily S Wilson; Marjorie M A de S...; Natasa Broit; Praphaporn Stewart; Daniel Shelley; Tracey McMahon; Steven M Ogbourne; Tam Hong Nguyen; Yi Chieh Lim; Alberto Pagani; Giovanni Appendino; Victoria A Gordon; Paul W Reddell; Glen M Boyle; Peter G Parsons
• Keywords: Immunogenic cell death; Immune checkpoint

Background Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection TT causes vascular disruption with concomitant tumor ablation in several preclinical models cancer, addition to tumors presenting veterinary clinic. completed Phase I dose escalation trials, some patients showing signs abscopal effects. However, exact molecular details underpinning its mechanism action (MoA), together immunotherapeutic potential oncology remain unclear. Methods A combination microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP phagocytosis assays and mixed lymphocyte reactions were used probe MoA vitro. In vivo studies MM649 xenograft, CT-26 immune checkpoint inhibitor refractory B16-F10-OVA bearing mice, latter or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated 4 (CTLA-4) mAb treatment. The effect at injected non-injected was also assessed. Results Here, we show induces endothelial cancer cells therapeutically relevant concentrations via caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate acts lipotoxin, binding promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading unfolded response mt/ER upregulation) subsequent depletion, organelle swelling, caspase activation, gasdermin E cleavage induction terminal necrosis. Consistent ER membranes, found promoted activation integrated stress release/externalization damage-associated patterns (HMGB1, ATP, calreticulin) from vitro vivo, characteristics indicative immunogenic (ICD). Confirmation ICD obtained through vaccination rechallenge experiments using colon carcinoma mice. Furthermore, reduced volume, induced infiltration, well improved survival mice when combined blockade. Conclusions These oncolytic small molecule multiple targets confirms by this compound augment antitumor responses immunotherapy.