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; Russell W. Jenkins

doi:10.1038/s41586-023-05704-6

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

Medicine

Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

Abstract

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking^1,2. 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 language	English
Pages (from-to)	158-167
Number of pages	10
Journal	Nature
Volume	615
Issue number	7950
DOIs	https://doi.org/10.1038/s41586-023-05704-6
State	Published - Mar 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Caspases
Drug Resistance, Neoplasm
Humans
Immune Evasion/genetics
Immunotherapy/methods
Interferon-gamma/immunology
Janus Kinases
Organoids
Programmed Cell Death 1 Receptor/antagonists & inhibitors
Protein Serine-Threonine Kinases/antagonists & inhibitors
STAT Transcription Factors
Spheroids, Cellular
Tumor Necrosis Factors/immunology

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1038/s41586-023-05704-6

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Sun, Y., Revach, O. Y., Anderson, S., Kessler, E. A., Wolfe, C. H., Jenney, A., Mills, C. E., Robitschek, E. J., Davis, T. G. R., Kim, S., Fu, A., Ma, X., Gwee, J., Tiwari, P., Du, P. P., Sindurakar, P., Tian, J., Mehta, A., Schneider, A. M., ... Jenkins, R. W. (2023). Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature, 615(7950), 158-167. https://doi.org/10.1038/s41586-023-05704-6

@article{eb3769698d2340f9ae496fc2cc00bdb2,

title = "Targeting TBK1 to overcome resistance to cancer immunotherapy",

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.",

keywords = "Caspases, Drug Resistance, Neoplasm, Humans, Immune Evasion/genetics, Immunotherapy/methods, Interferon-gamma/immunology, Janus Kinases, Organoids, Programmed Cell Death 1 Receptor/antagonists \& inhibitors, Protein Serine-Threonine Kinases/antagonists \& inhibitors, STAT Transcription Factors, Spheroids, Cellular, Tumor Necrosis Factors/immunology",

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

note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = mar,

doi = "10.1038/s41586-023-05704-6",

language = "الإنجليزيّة",

volume = "615",

pages = "158--167",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7950",

}

Sun, Y, Revach, OY, Anderson, S, Kessler, EA, Wolfe, CH, Jenney, A, Mills, CE, Robitschek, EJ, Davis, TGR, Kim, S, Fu, A, Ma, X, Gwee, J, Tiwari, P, Du, PP, Sindurakar, P, Tian, J, Mehta, A, Schneider, AM, Yizhak, K, Sade-Feldman, M, LaSalle, T, Sharova, T, Xie, H, Liu, S, Michaud, WA, Saad-Beretta, R, Yates, KB, Iracheta-Vellve, A, Spetz, JKE, Qin, X, Sarosiek, KA, Zhang, G, Kim, JW, Su, MY, Cicerchia, AM, Rasmussen, MQ, Klempner, SJ, Juric, D, Pai, SI, Miller, DM, Giobbie-Hurder, A, Chen, JH, Pelka, K, Frederick, DT, Stinson, S, Ivanova, E, Aref, AR, Paweletz, CP, Barbie, DA, Sen, DR, Fisher, DE, Corcoran, RB, Hacohen, N, Sorger, PK, Flaherty, KT, Boland, GM, Manguso, RT & Jenkins, RW 2023, 'Targeting TBK1 to overcome resistance to cancer immunotherapy', Nature, vol. 615, no. 7950, pp. 158-167. https://doi.org/10.1038/s41586-023-05704-6

TY - JOUR

T1 - Targeting TBK1 to overcome resistance to cancer immunotherapy

AU - Sun, Yi

AU - Revach, Or yam

AU - Anderson, Seth

AU - Kessler, Emily A.

AU - Wolfe, Clara H.

AU - Jenney, Anne

AU - Mills, Caitlin E.

AU - Robitschek, Emily J.

AU - Davis, Thomas G.R.

AU - Kim, Sarah

AU - Fu, Amina

AU - Ma, Xiang

AU - Gwee, Jia

AU - Tiwari, Payal

AU - Du, Peter P.

AU - Sindurakar, Princy

AU - Tian, Jun

AU - Mehta, Arnav

AU - Schneider, Alexis M.

AU - Yizhak, Keren

AU - Sade-Feldman, Moshe

AU - LaSalle, Thomas

AU - Sharova, Tatyana

AU - Xie, Hongyan

AU - Liu, Shuming

AU - Michaud, William A.

AU - Saad-Beretta, Rodrigo

AU - Yates, Kathleen B.

AU - Iracheta-Vellve, Arvin

AU - Spetz, Johan K.E.

AU - Qin, Xingping

AU - Sarosiek, Kristopher A.

AU - Zhang, Gao

AU - Kim, Jong Wook

AU - Su, Mack Y.

AU - Cicerchia, Angelina M.

AU - Rasmussen, Martin Q.

AU - Klempner, Samuel J.

AU - Juric, Dejan

AU - Pai, Sara I.

AU - Miller, David M.

AU - Giobbie-Hurder, Anita

AU - Chen, Jonathan H.

AU - Pelka, Karin

AU - Frederick, Dennie T.

AU - Stinson, Susanna

AU - Ivanova, Elena

AU - Aref, Amir R.

AU - Paweletz, Cloud P.

AU - Barbie, David A.

AU - Sen, Debattama R.

AU - Fisher, David E.

AU - Corcoran, Ryan B.

AU - Hacohen, Nir

AU - Sorger, Peter K.

AU - Flaherty, Keith T.

AU - Boland, Genevieve M.

AU - Manguso, Robert T.

AU - Jenkins, Russell W.

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

KW - Caspases

KW - Drug Resistance, Neoplasm

KW - Humans

KW - Immune Evasion/genetics

KW - Immunotherapy/methods

KW - Interferon-gamma/immunology

KW - Janus Kinases

KW - Organoids

KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors

KW - Protein Serine-Threonine Kinases/antagonists & inhibitors

KW - STAT Transcription Factors

KW - Spheroids, Cellular

KW - Tumor Necrosis Factors/immunology

UR - http://www.scopus.com/inward/record.url?scp=85148090710&partnerID=8YFLogxK

U2 - 10.1038/s41586-023-05704-6

DO - 10.1038/s41586-023-05704-6

M3 - مقالة

C2 - 36634707

SN - 0028-0836

VL - 615

SP - 158

EP - 167

JO - Nature

JF - Nature

IS - 7950

ER -

Targeting TBK1 to overcome resistance to cancer immunotherapy

Abstract

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

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