Targeting TBK1 to overcome resistance to cancer immunotherapy.
Yi SunOr-Yam RevachSeth AndersonEmily A KesslerClara H WolfeAnne JenneyCaitlin E MillsEmily J RobitschekThomas G R DavisSarah KimAmina FuXiang MaJia GweePayal TiwariPeter P DuPrincy SindurakarJun TianArnav MehtaAlexis M SchneiderKeren YizhakMoshe Sade-FeldmanThomas LaSalleTatyana SharovaHongyan XieShuming LiuWilliam A MichaudRodrigo Saad-BerettaKathleen B YatesArvin Iracheta-VellveJohan K E SpetzXingping QinKristopher A SarosiekGao ZhangJong Wook KimMack Y SuAngelina M CicerchiaMartin Q RasmussenSamuel J KlempnerDejan JuricSara I PaiDavid M MillerAnita Giobbie-HurderJonathan H ChenKarin PelkaDennie T FrederickSusanna StinsonElena IvanovaAmir R ArefCloud P PaweletzDavid A BarbieDebattama R SenDavid E FisherRyan B CorcoranNir HacohenPeter K SorgerKeith T FlahertyGenevieve M BolandRobert T MangusoRussell William JenkinsPublished in: Nature (2023)
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 screen 4 . 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.