Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8 + T Cells in Immunotherapy-Resistant and Metastatic Cancers.

Autor: Dunn J; Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., McCuaig RD; Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Tan AHY; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Tu WJ; Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Wu F; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Wagstaff KM; Cancer Targeting and Nuclear Therapeutics Lab, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia., Zafar A; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Ali S; Medical Oncology, St John of God Midland Public and Private Hospitals, Perth, WA 6056, Australia., Diwakar H; Woden Specialist Medical Centre, I-MED Radiology Network, Canberra, ACT 2606, Australia., Dahlstrom JE; Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra Health Services, Canberra, ACT 2605, Australia.; ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia.; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia., Bean EG; Anatomical Pathology, ACT Pathology, The Canberra Hospital, Canberra Health Services, Canberra, ACT 2605, Australia., Forwood JK; School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia., Tsimbalyuk S; School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia., Cross EM; School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia., Hardy K; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia., Bain AL; Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia., Ahern E; Department of Medical Oncology, Monash Health and Monash University, Melbourne, VIC 3168, Australia.; Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia., Dolcetti R; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.; Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC 3010, Australia.; The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia., Mazzieri R; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.; The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia., Yip D; ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia.; Department of Medical Oncology, Canberra Health Services, The Canberra Hospital, Canberra, ACT 2605, Australia., Eastgate M; Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.; Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia., Malik L; ANU Medical School, College of Health and Medicine, The Australian National University, Canberra, ACT 0200, Australia.; Department of Medical Oncology, Canberra Health Services, The Canberra Hospital, Canberra, ACT 2605, Australia., Milburn P; The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia., Jans DA; Nuclear Signaling Lab, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia., Rao S; Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.; Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Mar 21; Vol. 14 (6). Date of Electronic Publication: 2022 Mar 21.
DOI: 10.3390/cancers14061596
Abstrakt: Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ 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-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ 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-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1 + /CD8 + T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ 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-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8 + T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje