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https://repository.monashhealth.org/monashhealthjspui/handle/1/47717| Title: | Selective Targeting of Protein Kinase C (PKC)-theta Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8+ T Cells in Immunotherapy-Resistant and Metastatic Cancers. | Authors: | Dunn J.;McCuaig R.D.;Tan A.H.Y.;Tu W.J.;Wu F.;Wagstaff K.M.;Zafar A.;Ali S.;Diwakar H.;Dahlstrom J.E.;Bean E.G.;Forwood J.K.;Tsimbalyuk S.;Cross E.M.;Hardy K.;Bain A.L.;Ahern E.;Dolcetti R.;Mazzieri R.;Yip D.;Eastgate M.;Malik L.;Milburn P.;Jans D.A.;Rao S. | Monash Health Department(s): | Oncology | Institution: | (Dunn, McCuaig, Tu, Bain, Rao) Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia (Dunn, McCuaig, Tan, Tu, Wu, Zafar, Hardy, Rao) Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Bruce, ACT 2617, Australia (Wagstaff) Cancer Targeting and Nuclear Therapeutics Lab, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia (Ali) Medical Oncology, St John of God Midland Public and Private Hospitals, Midland, WA 6056, Australia (Diwakar) Woden Specialist Medical Centre, I-MED Radiology Network, Canberra, ACT 2606, Australia (Dahlstrom, Bean) Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra Health Services, Garran, ACT 2605, Australia (Dahlstrom, Yip, Malik) ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia (Dahlstrom, Milburn) The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia (Forwood, Tsimbalyuk, Cross) School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia (Ahern) Department of Medical Oncology, Monash Health and Monash University, Clayton, VIC 3168, Australia (Ahern) Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia (Dolcetti, Mazzieri) Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia (Dolcetti) Sir Peter MacCallum Department of Oncology, The University of Melbourne, VIC 3010, Australia (Dolcetti) Department of Microbiology and Immunology, The University of Melbourne, VIC 3010, Australia (Dolcetti, Mazzieri) The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia (Yip, Malik) Department of Medical Oncology, Canberra Health Services, The Canberra Hospital, Garran, ACT 2605, Australia (Eastgate) Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia (Eastgate) Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia (Jans) Nuclear Signaling Lab, Department of Biochemistry and & Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia |
Issue Date: | 6-May-2022 | Copyright year: | 2022 | Publisher: | MDPI | Place of publication: | Switzerland | Publication information: | Cancers. 14(6) (no pagination), 2022. Article Number: 1596. Date of Publication: March-2 2022. | Journal: | Cancers | Abstract: | Protein kinase C (PKC)-theta is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-theta (nPKC-theta) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-theta is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-theta, we designed a novel PKC-theta peptide inhibitor (nPKC-thetai2) that selectively inhibits nPKC-theta nuclear translocation but not PKC-theta signaling in healthy T cells. Targeting nPKC-theta reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-theta was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-theta complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-thetai2 inhibited the ZEB1/PKC-theta repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-theta mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-theta but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. | DOI: | http://monash.idm.oclc.org/login?url=https://dx.doi.org/10.3390/cancers14061596 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/47717 | Type: | Article | Subjects: | brain metastasis cancer immunotherapy cancer cancer resistance cancer stem cell CD8+ T lymphocyte circulating tumor cell cytokine production epithelial mesenchymal transition liquid biopsy MCF-7 cell line MDA-MB-231 cell line metastasis metastatic melanoma nuclear import nuclear localization signal protein localization triple negative breast cancer docetaxel ipilimumab karyopherin nivolumab pembrolizumab programmed 1 receptor protein kinase C inhibitor protein kinase C theta transcription factor ZEB1 mPKC thetai2 |
Type of Clinical Study or Trial: | Observational study (cohort, case-control, cross sectional, or survey) |
| Appears in Collections: | Articles |
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