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Targeting TBK1 to overcome resistance to cancer immunotherapy

Author

Listed:
  • Yi Sun

    (Massachusetts General Hospital, Harvard Medical School)

  • Or-yam Revach

    (Massachusetts General Hospital, Harvard Medical School)

  • Seth Anderson

    (Broad Institute of MIT and Harvard)

  • Emily A. Kessler

    (Broad Institute of MIT and Harvard)

  • Clara H. Wolfe

    (Broad Institute of MIT and Harvard)

  • Anne Jenney

    (Harvard Medical School)

  • Caitlin E. Mills

    (Harvard Medical School)

  • Emily J. Robitschek

    (Broad Institute of MIT and Harvard)

  • Thomas G. R. Davis

    (Broad Institute of MIT and Harvard)

  • Sarah Kim

    (Broad Institute of MIT and Harvard)

  • Amina Fu

    (Massachusetts General Hospital, Harvard Medical School)

  • Xiang Ma

    (Massachusetts General Hospital, Harvard Medical School)

  • Jia Gwee

    (Massachusetts General Hospital, Harvard Medical School)

  • Payal Tiwari

    (Broad Institute of MIT and Harvard)

  • Peter P. Du

    (Broad Institute of MIT and Harvard)

  • Princy Sindurakar

    (Massachusetts General Hospital, Harvard Medical School)

  • Jun Tian

    (Massachusetts General Hospital, Harvard Medical School)

  • Arnav Mehta

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Alexis M. Schneider

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • Keren Yizhak

    (Technion)

  • Moshe Sade-Feldman

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Thomas LaSalle

    (Massachusetts General Hospital, Harvard Medical School)

  • Tatyana Sharova

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Hongyan Xie

    (Massachusetts General Hospital, Harvard Medical School)

  • Shuming Liu

    (Harvard Medical School)

  • William A. Michaud

    (Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Rodrigo Saad-Beretta

    (Massachusetts General Hospital, Harvard Medical School)

  • Kathleen B. Yates

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Arvin Iracheta-Vellve

    (Broad Institute of MIT and Harvard)

  • Johan K. E. Spetz

    (Harvard Medical School
    Harvard School of Public Health
    Harvard School of Public Health)

  • Xingping Qin

    (Harvard Medical School
    Harvard School of Public Health
    Harvard School of Public Health)

  • Kristopher A. Sarosiek

    (Harvard Medical School
    Harvard School of Public Health
    Harvard School of Public Health)

  • Gao Zhang

    (The Wistar Institute
    Duke University School of Medicine
    Duke University School of Medicine)

  • Jong Wook Kim

    (UC San Diego
    UC San Diego
    UC San Diego)

  • Mack Y. Su

    (Massachusetts General Hospital and Harvard Medical School)

  • Angelina M. Cicerchia

    (Massachusetts General Hospital, Harvard Medical School)

  • Martin Q. Rasmussen

    (Massachusetts General Hospital, Harvard Medical School)

  • Samuel J. Klempner

    (Massachusetts General Hospital, Harvard Medical School)

  • Dejan Juric

    (Massachusetts General Hospital, Harvard Medical School)

  • Sara I. Pai

    (Massachusetts General Hospital Cancer Center, Harvard Medical School
    Massachusetts General Hospital)

  • David M. Miller

    (Massachusetts General Hospital, Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Anita Giobbie-Hurder

    (Dana-Farber Cancer Institute)

  • Jonathan H. Chen

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Karin Pelka

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Dennie T. Frederick

    (Massachusetts General Hospital, Harvard Medical School)

  • Susanna Stinson

    (Gilead Sciences)

  • Elena Ivanova

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Amir R. Aref

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Xsphera Biosciences)

  • Cloud P. Paweletz

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • David A. Barbie

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Debattama R. Sen

    (Massachusetts General Hospital, Harvard Medical School)

  • David E. Fisher

    (Massachusetts General Hospital and Harvard Medical School)

  • Ryan B. Corcoran

    (Massachusetts General Hospital, Harvard Medical School)

  • Nir Hacohen

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Peter K. Sorger

    (Harvard Medical School)

  • Keith T. Flaherty

    (Massachusetts General Hospital, Harvard Medical School)

  • Genevieve M. Boland

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital Cancer Center, Harvard Medical School)

  • Robert T. Manguso

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Russell W. Jenkins

    (Massachusetts General Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School)

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.

Suggested Citation

  • 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 & Pa, 2023. "Targeting TBK1 to overcome resistance to cancer immunotherapy," Nature, Nature, vol. 615(7950), pages 158-167, March.
    • Handle: RePEc:nat:nature:v:615:y:2023:i:7950:d:10.1038_s41586-023-05704-6
    DOI: 10.1038/s41586-023-05704-6
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    Cited by:

    1. Jonas Engesser & Robin Khatri & Darius P. Schaub & Yu Zhao & Hans-Joachim Paust & Zeba Sultana & Nariaki Asada & Jan-Hendrik Riedel & Varshi Sivayoganathan & Anett Peters & Anna Kaffke & Saskia-Lariss, 2024. "Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Jong Ho Park & Mahsa Mortaja & Heehwa G. Son & Xutu Zhao & Lauren M. Sloat & Marjan Azin & Jun Wang & Michael R. Collier & Krishna S. Tummala & Anna Mandinova & Nabeel Bardeesy & Yevgeniy R. Semenov &, 2024. "Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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