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Published VersionCC BY-NC V4.0, Open Access
Journal article
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
Journal for Immunotherapy of Cancer, Vol.12(4), pp.1-17
2024
PMID: 38658031
Abstract
BackgroundTigilanol 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.MethodsA 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.ResultsHere, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein responsemt/ER 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 activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade.ConclusionsThese data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy.
Details
- Title
- 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
- Authors
- Jason K Cullen (Corresponding Author) - QIMR Berghofer Medical Research InstitutePei-Yi Yap - QIMR Berghofer Medical Research InstituteBlake Ferguson - QIMR Berghofer Medical Research InstituteZara C Bruce - QIMR Berghofer Medical Research InstituteMotoko Koyama - QIMR Berghofer Medical Research InstituteHerlina Handoko - QIMR Berghofer Medical Research InstituteKevin Hendrawan - QIMR Berghofer Medical Research InstituteJacinta L Simmons - QIMR Berghofer Medical Research InstituteKelly M Brooks - QIMR Berghofer Medical Research InstituteJenny Johns - QIMR Berghofer Medical Research InstituteEmily S Wilson - QIMR Berghofer Medical Research InstituteMarjorie M A de Souza - QIMR Berghofer Medical Research InstituteNatasa Broit - QIMR Berghofer Medical Research InstitutePraphaporn Stewart - University of the Sunshine Coast, Queensland, Centre for BioinnovationDaniel Shelley - University of the Sunshine Coast, Queensland, Technical and Work Integrated Learning (WIL) Operations - LegacyTracey McMahon - University of the Sunshine Coast, Queensland, Centre for BioinnovationSteven M Ogbourne - University of the Sunshine Coast, Queensland, Centre for BioinnovationTam Hong Nguyen - QIMR Berghofer Medical Research InstituteYi Chieh Lim - Danish Cancer SocietyAlberto Pagani - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”Giovanni Appendino - Università degli Studi del Piemonte Orientale “Amedeo Avogadro”Victoria A Gordon - QBiotics Group Ltd.Paul W Reddell - QBiotics Group Ltd.Glen M Boyle - QIMR Berghofer Medical Research InstitutePeter G Parsons - QIMR Berghofer Medical Research Institute
- Publication details
- Journal for Immunotherapy of Cancer, Vol.12(4), pp.1-17
- Publisher
- BMJ Group
- Date published
- 2024
- DOI
- 10.1136/jitc-2022-006602
- ISSN
- 2051-1426
- PMID
- 38658031
- Copyright note
- © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
- Data Availability
- Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data generated and analyzed during this study are contained within the published article and its Supplementary Information file. All materials are available on reasonable request and negotiation of an MTA with QBiotics Group Ltd.
- Organisation Unit
- GeneCology Research Centre - Legacy; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 991023098202621
- Output Type
- Journal article
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