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

Dunn, J; McCuaig, RD; Tan, AHY; Tu, WJ; Wu, F; Wagstaff, KM; Zafar, A; Ali, S; Diwakar, H; Dahlstrom, JE; Bean, EG; Forwood, JK; Tsimbalyuk, S; Cross, EM; Hardy, K; Bain, AL; Ahern, E; Dolcetti, R; Mazzieri, R; Yip, D; Eastgate, M; Malik, L; Milburn, P; Jans, DA; Rao, S

Author(s): Dunn, J; McCuaig, RD; Tan, AHY; Tu, WJ; Wu, F; Wagstaff, KM; Zafar, A; Ali, S; Diwakar, H; Dahlstrom, JE; Bean, EG; Forwood, JK; Tsimbalyuk, S; Cross, EM; Hardy, K; Bain, AL; Ahern, E; Dolcetti, R; Mazzieri, R; Yip, D; Eastgate, M; Malik, L; Milburn, P; Jans, DA; Rao, S;
Details: Publication Year 2022-03-21,Volume 14,Issue #6,Page 1596
Journal Title: Cancers
Publication Type: Research article
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.
Keywords: T cell; breast cancer; cancer stem cell; epithelial-to-mesenchymal transition; immunotherapy; melanoma; metastasis; nuclear translocation; protein kinase C (PKC)-theta; resistance
Department(s): Laboratory Research
PubMed ID: 35326747
Publisher's Version: https://doi.org/10.3390/cancers14061596
Open Access at Publisher's Site: https://doi.org/10.3390/cancers14061596
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-24 01:12:13

Last Modified: 2024-10-24 01:14:10