1. Academic Validation
  2. Targeting TBK1 to overcome resistance to cancer immunotherapy

Targeting TBK1 to overcome resistance to cancer immunotherapy

  • Nature. 2023 Jan 12. doi: 10.1038/s41586-023-05704-6.
Yi Sun 1 Or-Yam Revach 1 Seth Anderson 2 Emily A Kessler 2 Clara H Wolfe 2 Anne Jenney 3 Caitlin E Mills 3 Emily J Robitschek 2 Thomas G R Davis 2 Sarah Kim 2 Amina Fu 1 Xiang Ma 1 Jia Gwee 1 Payal Tiwari 2 Peter P Du 2 Princy Sindurakar 1 Jun Tian 1 Arnav Mehta 1 2 4 Alexis M Schneider 2 5 Keren Yizhak 6 Moshe Sade-Feldman 1 2 Thomas LaSalle 1 Tatyana Sharova 7 Hongyan Xie 1 Shuming Liu 3 William A Michaud 7 Rodrigo Saad-Beretta 1 Kathleen B Yates 1 2 Arvin Iracheta-Vellve 2 Johan K E Spetz 3 8 9 Xingping Qin 3 8 9 Kristopher A Sarosiek 3 8 9 Gao Zhang 10 11 Jong Wook Kim 12 Mack Y Su 13 Angelina M Cicerchia 1 Martin Q Rasmussen 1 Samuel J Klempner 1 Dejan Juric 1 Sara I Pai 7 14 David M Miller 1 15 Anita Giobbie-Hurder 16 Jonathan H Chen 1 2 17 Karin Pelka 1 2 Dennie T Frederick 1 Susanna Stinson 18 Elena Ivanova 4 19 Amir R Aref 4 19 20 Cloud P Paweletz 4 19 David A Barbie 4 19 Debattama R Sen 1 David E Fisher 13 Ryan B Corcoran 1 Nir Hacohen 1 2 Peter K Sorger 3 Keith T Flaherty 1 Genevieve M Boland 2 7 Robert T Manguso 1 2 Russell W Jenkins 21 22 23
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 3 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6 Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Institute of Technology, Technion, Haifa, Israel.
  • 7 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 8 Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.
  • 9 John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA.
  • 10 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 11 Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • 12 Moores Cancer Center, Center for Novel Therapeutics and Department of Medicine, UC San Diego, La Jolla, CA, USA.
  • 13 Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 14 Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
  • 15 Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 16 Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 17 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • 18 Gilead Sciences, Foster City, CA, USA.
  • 19 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 20 Xsphera Biosciences, Boston, MA, USA.
  • 21 Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected]
  • 22 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  • 23 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA. [email protected]
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.

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