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
  • 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].
PMID: 36634707 DOI: 10.1038/s41586-023-05704-6
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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