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 Yizhak, Moshe 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 and Russell W. Jenkins ()
Additional contact information
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
Alexis M. Schneider: Broad Institute of MIT and Harvard
Keren Yizhak: Technion
Moshe Sade-Feldman: Massachusetts General Hospital, Harvard Medical School
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
Arvin Iracheta-Vellve: Broad Institute of MIT and Harvard
Johan K. E. Spetz: Harvard Medical School
Xingping Qin: Harvard Medical School
Kristopher A. Sarosiek: Harvard Medical School
Gao Zhang: The Wistar Institute
Jong Wook Kim: 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
David M. Miller: Massachusetts General Hospital, Harvard Medical School
Anita Giobbie-Hurder: Dana-Farber Cancer Institute
Jonathan H. Chen: Massachusetts General Hospital, Harvard Medical School
Karin Pelka: Massachusetts General Hospital, Harvard Medical School
Dennie T. Frederick: Massachusetts General Hospital, Harvard Medical School
Susanna Stinson: Gilead Sciences
Elena Ivanova: Dana-Farber Cancer Institute
Amir R. Aref: Dana-Farber Cancer Institute
Cloud P. Paweletz: Dana-Farber Cancer Institute
David A. Barbie: 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
Peter K. Sorger: Harvard Medical School
Keith T. Flaherty: Massachusetts General Hospital, Harvard Medical School
Genevieve M. Boland: Broad Institute of MIT and Harvard
Robert T. Manguso: Massachusetts General Hospital, Harvard Medical School
Russell W. Jenkins: Massachusetts General Hospital, Harvard Medical School

Nature, 2023, vol. 615, issue 7950, 158-167

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05704-6

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