Targeting TBK1 to overcome resistance to cancer immunotherapy

被引：94

作者：

Sun, Yi ^{[1
]}

Revach, Or-yam ^{[1
]}

Anderson, Seth ^{[2
]}

Kessler, Emily A. A. ^{[2
]}

Wolfe, Clara H. H. ^{[2
]}

Jenney, Anne ^{[3
]}

Mills, Caitlin E. E. ^{[3
]}

Robitschek, Emily J. J.

Davis, Thomas G. R. ^{[2
]}

Kim, Sarah ^{[2
]}

Fu, Amina ^{[1
]}

Ma, Xiang ^{[1
]}

Gwee, Jia ^{[1
]}

Tiwari, Payal ^{[2
]}

Du, Peter P. P.

Sindurakar, Princy ^{[1
]}

Tian, Jun ^{[1
]}

Mehta, Arnav ^{[1
,2
,4
]}

Schneider, Alexis M. M. ^{[2
,5
]}

Yizhak, Keren ^{[6
]}

Sade-Feldman, Moshe ^{[1
,2
]}

LaSalle, Thomas ^{[1
]}

Sharova, Tatyana ^{[7
]}

Xie, Hongyan ^{[1
]}

Liu, Shuming ^{[3
]}

Michaud, William A. A. ^{[7
]}

Saad-Beretta, Rodrigo ^{[1
]}

Yates, Kathleen B. B. ^{[1
,2
]}

Iracheta-Vellve, Arvin ^{[2
]}

Spetz, Johan K. E. ^{[3
,8
,9
]}

Qin, Xingping ^{[3
,8
,9
]}

Sarosiek, Kristopher A. A. ^{[3
,8
,9
]}

Zhang, Gao ^{[10
,11
,12
]}

Kim, Jong Wook ^{[13
,14
,15
]}

Su, Mack Y. Y. ^{[16
]}

Cicerchia, Angelina M. M. ^{[1
]}

Rasmussen, Martin Q. Q.

Klempner, Samuel J. J.

Juric, Dejan ^{[1
]}

Pai, Sara I. I.

Miller, David M. M.

Giobbie-Hurder, Anita ^{[17
]}

Chen, Jonathan H. H. ^{[1
,2
,18
]}

Pelka, Karin ^{[1
,2
]}

Frederick, Dennie T. T. ^{[1
]}

Stinson, Susanna ^{[19
]}

Ivanova, Elena ^{[4
]}

Aref, Amir R. R.

Paweletz, Cloud P. P.

Barbie, David A. A.

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[5] MIT, Dept Biol Engn, Cambridge, MA USA

[6] Technion, Inst Technol, Rappaport Fac Med, Dept Cell Biol & Canc Sci, Haifa, Israel

[7] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Dept Surg, Div Surg Oncol, Boston, MA USA

[8] Harvard Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA USA

[9] Harvard Sch Publ Hlth, John B Little Ctr Radiat Sci, Boston, MA USA

[10] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA USA

[11] Duke Univ, Preston Robert Brain Tumor Ctr T, Dept Neurosurg, Sch Med, Durham, NC USA

[12] Duke Univ, Preston Robert Tisch Brain Tumor Ctr, Dept Pathol, Sch Med, Durham, NC USA

[13] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA

[14] Univ Calif San Diego, Ctr Novel Therapeut, La Jolla, CA USA

[15] Univ Calif San Diego, Dept Med, La Jolla, CA USA

[16] Harvard Med Sch, Boston, MA USA

[17] Dana Farber Canc Inst, Dept Data Sci, Div Biostat, Boston, MA USA

[18] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA

[19] Gilead Sci, Foster City, CA USA

来源：

NATURE | 2023年 / 615卷 / 7950期

关键词：

EXPRESSION; DESIGN; CELLS; CGAS;

D O I：

10.1038/s41586-023-05704-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 screen(4). 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 IFN gamma). 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 IFN gamma in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

引用

页码：158 / +

页数：32

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