دورية أكاديمية
أعرض في EDS

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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Cullen JK; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia Jason.Cullen@qbiotics.com.; The University of Queensland, Brisbane, Queensland, Australia.; QBiotics Group Limited, Brisbane, Queensland, Australia., Yap PY; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Ferguson B; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Bruce ZC; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Koyama M; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Handoko H; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Hendrawan K; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Simmons JL; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; The University of Queensland, Brisbane, Queensland, Australia., Brooks KM; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Johns J; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Wilson ES; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., de Souza MMA; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Broit N; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Stewart P; University of the Sunshine Coast, Maroochydore DC, Queensland, Australia., Shelley D; University of the Sunshine Coast, Maroochydore DC, Queensland, Australia., McMahon T; University of the Sunshine Coast, Maroochydore DC, Queensland, Australia., Ogbourne SM; QBiotics Group Limited, Brisbane, Queensland, Australia.; University of the Sunshine Coast, Maroochydore DC, Queensland, Australia., Nguyen TH; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Lim YC; Danish Cancer Society Research Centre, Copenhagen DK, Denmark., Pagani A; Dipartimento di Scienze del Farmaco, Università Degli Studi del Piemonte Orientale, Novara, Italy., Appendino G; Dipartimento di Scienze del Farmaco, Università Degli Studi del Piemonte Orientale, Novara, Italy., Gordon VA; QBiotics Group Limited, Brisbane, Queensland, Australia., Reddell PW; QBiotics Group Limited, Brisbane, Queensland, Australia., Boyle GM; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; The University of Queensland, Brisbane, Queensland, Australia., Parsons PG; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; QBiotics Group Limited, Brisbane, Queensland, Australia.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Apr 24; Vol. 12 (4). Date of Electronic Publication: 2024 Apr 24.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: Immunogenic Cell Death*/drug effects , Immune Checkpoint Inhibitors*/pharmacology , Immune Checkpoint Inhibitors*/therapeutic use, Animals ; Mice ; Humans ; Cell Line, Tumor ; Female ; Xenograft Model Antitumor Assays ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/therapy
مستخلص: 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: Here, 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 response mt/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.
Conclusions: These 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.
Competing Interests: Competing interests: JKC and GMB were previous recipients of research fellowships co-sponsored by QBiotics Group Ltd. GMB, GA and PGP are recipients of current contract research funding from QBiotics Group Ltd. PWR, SMO, VAG and PGP are employees of QBiotics Group Ltd. JKC became a QBiotics employee during the review process. JKC, P-YY, JJ, GMB, SMO, PWR, VAG and PGP are shareholders in QBiotics Group Ltd. The other authors declare no competing interests. The work described in this study forms the basis of two international patents: PCT/AU2020/050360, PCT/AU2018/050277.
(© 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.)
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معلومات مُعتمدة: 75N92020D00005 United States HL NHLBI NIH HHS; 75N93022D00005 United States AI NIAID NIH HHS; 75N99020D00005 United States OF ORFDO NIH HHS; 75N95020D00005 United States DA NIDA NIH HHS; 75N93023D00005 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: Cytotoxicity, Immunologic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Immune Checkpoint Inhibitors; Lymphocytes, Tumor-Infiltrating
المشرفين على المادة: 0 (Immune Checkpoint Inhibitors)
تواريخ الأحداث: Date Created: 20240424 Date Completed: 20240424 Latest Revision: 20240901
رمز التحديث: 20240901
مُعرف محوري في PubMed: PMC11043783
DOI: 10.1136/jitc-2022-006602
PMID: 38658031
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2022-006602