Abstract
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 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.
Original language | English |
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Pages (from-to) | 158-167 |
Number of pages | 10 |
Journal | Nature |
Volume | 615 |
Issue number | 7950 |
DOIs | |
State | Published - Mar 2023 |
Keywords
- Humans
- Immune Evasion/genetics
- Immunotherapy/methods
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Organoids
- Drug Resistance, Neoplasm
- Tumor Necrosis Factors/immunology
- Interferon-gamma/immunology
- Spheroids, Cellular
- Caspases
- Janus Kinases
- STAT Transcription Factors
ASJC Scopus subject areas
- General