Targeting TBK1 to overcome resistance to cancer immunotherapy

Yi Sun, Or yam Revach, Seth Anderson, Emily A. Kessler, Clara H. Wolfe, Anne Jenney, Caitlin E. Mills, Emily J. Robitschek, Thomas G.R. Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter P. Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Alexis M. Schneider, Keren YizhakMoshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, Shuming Liu, William A. Michaud, Rodrigo Saad-Beretta, Kathleen B. Yates, Arvin Iracheta-Vellve, Johan K.E. Spetz, Xingping Qin, Kristopher A. Sarosiek, Gao Zhang, Jong Wook Kim, Mack Y. Su, Angelina M. Cicerchia, Martin Q. Rasmussen, Samuel J. Klempner, Dejan Juric, Sara I. Pai, David M. Miller, Anita Giobbie-Hurder, Jonathan H. Chen, Karin Pelka, Dennie T. Frederick, Susanna Stinson, Elena Ivanova, Amir R. Aref, Cloud P. Paweletz, David A. Barbie, Debattama R. Sen, David E. Fisher, Ryan B. Corcoran, Nir Hacohen, Peter K. Sorger, Keith T. Flaherty, Genevieve M. Boland, Robert T. Manguso, Russell W. Jenkins

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)158-167
Number of pages10
JournalNature
Volume615
Issue number7950
DOIs
StatePublished - 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

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