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

作者：Jason K. Cullen, Pei-Yi Yap, Blake Ferguson, Zara C. Bruce, Motoko Koyama, Herlina Y. Handoko, Kevin Hendrawan, Jacinta L. Simmons, Kelly Brooks, Jenny Johns, Emily Wilson, Marjorie M. A. de Souza, Natasa Broit, Praphaporn Stewart, Daniel J. Shelley, Tracey R. McMahon, Steven M. Ogbourne, Tam Nguyen, Yi Chieh Lim, Alberto Pagani, Giovanni Appendino, Victoria Gordon, Paul Reddell, Glen M. Boyle, Peter G. Parsons · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2022-006602 · 被引用次数：13 · 研究领域：Cancer Research and Treatments、Colorectal and Anal Carcinomas、Tannin, Tannase and Anticancer Activities

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 of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear. METHODS: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed. RESULTS: upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted...