Targeting TBK1 to overcome resistance to cancer immunotherapy
Nature, 2023
Sun Y., Revach O., Anderson S., Kessler E., Wolfe C., Jenney A., Mills C., Robitschek E., Davis T., Kim S., Fu A., Ma X., Gwee J., Tiwari P., Du P., Sindurakar P., Tian J., Mehta A., Schneider A., Yizhak K., Sade-Feldman M., LaSalle T., Sharova T., Xie H., Liu S., Michaud W., Saad-Beretta R., Yates K., Iracheta-Vellve A., Spetz J., Qin X., Sarosiek K., Zhang G., Kim J., Su M., Cicerchia A., Rasmussen M., Klempner S., Juric D., Pai S., Miller D., Giobbie-Hurder A., Chen J., Pelka K., Frederick D., Stinson S., Ivanova E., Aref A., Paweletz C., Barbie D., Sen D., Fisher D., Corcoran R., Hacohen N., Sorger P., Flaherty K., Boland G., Manguso R., Jenkins R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Pathophysiology | Plasma |  Olink Explore 3072/384 |
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. We identified 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 pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/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 (PDOTS) and matched patient-derived organoids (PDOs). Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.