Intracellular zinc protects tumours from T cell-mediated cytotoxicity

Lelliott, EJ; Naddaf, J; Ganio, K; Michie, J; Wang, S; Liu, L; Silke, N; Ahn, A; Ramsbottom, KM; Brennan, AJ; Freeman, AJ; Goel, S; Vervoort, SJ; Kearney, CJ; Beavis, PA; McDevitt, CA; Silke, J; Oliaro, J

Author(s): Lelliott, EJ; Naddaf, J; Ganio, K; Michie, J; Wang, S; Liu, L; Silke, N; Ahn, A; Ramsbottom, KM; Brennan, AJ; Freeman, AJ; Goel, S; Vervoort, SJ; Kearney, CJ; Beavis, PA; McDevitt, CA; Silke, J; Oliaro, J;
Details: Publication Year 2024-12,Volume 31,Issue #12,Page 1707-1716
Journal Title: Cell Death & Differentiation
Abstract: Tumour immune evasion presents a significant challenge to the effectiveness of cancer immunotherapies. Recent advances in high-throughput screening techniques have uncovered that loss of antigen presentation and cytokine signalling pathways are central mechanisms by which tumours evade T cell immunity. To uncover additional vulnerabilities in tumour cells beyond the well-recognized antigen presentation pathway, we conducted a genome-wide CRISPR/Cas9 screen to identify genes that mediate resistance to chimeric-antigen receptor (CAR)-T cells, which function independently of classical antigen presentation. Our study revealed that loss of core-binding factor subunit beta (CBFbeta) enhances tumour cell resistance to T cell killing, mediated through T cell-derived TNF. Mechanistically, RNA-sequencing and elemental analyses revealed that deletion of CBFbeta disrupts numerous pathways including those involved in zinc homoeostasis. Moreover, we demonstrated that modulation of cellular zinc, achieved by supplementation or chelation, significantly altered tumour cell susceptibility to TNF by regulating the levels of inhibitor of apoptosis proteins. Consistent with this, treatment of tumour cells with a membrane-permeable zinc chelator had no impact on tumour cell viability alone, but significantly increased tumour cell lysis by CD8+ T cells in a TNF-dependent but perforin-independent manner. These results underscore the crucial role of intracellular zinc in regulating tumour cell susceptibility to T cell-mediated killing, revealing a novel vulnerability in tumour cells that might be exploited for the development of future cancer immunotherapeutics.
Publisher: Springer Nature
Keywords: *Zinc/metabolism/pharmacology; Humans; Animals; Cell Line, Tumor; Tumor Necrosis Factor-alpha/metabolism; Mice; Neoplasms/immunology/metabolism/pathology/drug therapy; CD8-Positive T-Lymphocytes/immunology/metabolism/drug effects; Cytotoxicity, Immunologic/drug effects; CRISPR-Cas Systems
Research Division(s): Inflammation
PubMed ID: 39261596
Publisher's Version: https://doi.org/10.1038/s41418-024-01369-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41418-024-01369-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41418-024-01369-4.pdf - (4.48MB, application/pdf)

Creation Date: 2024-10-04 10:45:04

Last Modified: 2025-01-21 11:04:33