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Targeting TBK1 to overcome resistance to cancer immunotherapy.

ABSTRACT: Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking^1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)³ as a candidate immune-evasion gene in a pooled genetic screen⁴. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

SUBMITTER: Sun Y

PROVIDER: S-EPMC10171827 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Targeting TBK1 to overcome resistance to cancer immunotherapy.

Sun Yi Y Revach Or-Yam OY Anderson Seth S Kessler Emily A EA Wolfe Clara H CH Jenney Anne A Mills Caitlin E CE Robitschek Emily J EJ Davis Thomas G R TGR Kim Sarah S Fu Amina A Ma Xiang X Gwee Jia J Tiwari Payal P Du Peter P PP Sindurakar Princy P Tian Jun J Mehta Arnav A Schneider Alexis M AM Yizhak Keren K Sade-Feldman Moshe M LaSalle Thomas T Sharova Tatyana T Xie Hongyan H Liu Shuming S Michaud William A WA Saad-Beretta Rodrigo R Yates Kathleen B KB Iracheta-Vellve Arvin A Spetz Johan K E JKE Qin Xingping X Sarosiek Kristopher A KA Zhang Gao G Kim Jong Wook JW Su Mack Y MY Cicerchia Angelina M AM Rasmussen Martin Q MQ Klempner Samuel J SJ Juric Dejan D Pai Sara I SI Miller David M DM Giobbie-Hurder Anita A Chen Jonathan H JH Pelka Karin K Frederick Dennie T DT Stinson Susanna S Ivanova Elena E Aref Amir R AR Paweletz Cloud P CP Barbie David A DA Sen Debattama R DR Fisher David E DE Corcoran Ryan B RB Hacohen Nir N Sorger Peter K PK Flaherty Keith T KT Boland Genevieve M GM Manguso Robert T RT Jenkins Russell W RW

Nature 20230112 7950

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhan ...[more]

PMID: 36634707

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Project description:PurposeThe overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity.ResultsSignificant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1).ConclusionsOur study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.

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Targeting TBK1 to overcome resistance to cancer immunotherapy.

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Targeting TBK1 to overcome resistance to cancer immunotherapy.

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