Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity

被引:283
|
作者
Sivick, Kelsey E. [1 ]
Desbien, Anthony L. [1 ]
Glickman, Laura Hix [1 ,4 ]
Reiner, Gabrielle L. [1 ]
Corrales, Leticia [1 ]
Surh, Natalie H. [1 ]
Hudson, Thomas E. [1 ,5 ]
Vu, Uyen T. [1 ,6 ]
Francica, Brian J. [1 ]
Banda, Tamara [1 ]
Katibah, George E. [1 ]
Kanne, David B. [1 ]
Leong, Justin J. [1 ]
Metchette, Ken [1 ]
Bruml, Jacob R. [1 ]
Ndubaku, Chudi O. [1 ]
McKenna, Jeffrey M. [2 ]
Feng, Yan [2 ]
Zheng, Lianxing [2 ]
Bender, Steven L. [3 ]
Cho, Charles Y. [3 ]
Leong, Meredith L. [1 ]
van Elsas, Andrea [1 ]
Dubensky, Thomas W., Jr. [1 ,7 ]
McWhirter, Sarah M. [1 ]
机构
[1] Aduro Biotech Inc, Berkeley, CA 94710 USA
[2] Novartis Inst BioMed Res, Cambridge, MA 02139 USA
[3] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
[4] Actym Therapeut Inc, Berkeley, CA 94710 USA
[5] Gilead Sci Inc, Foster City, CA 94404 USA
[6] Touro Univ Nevada, Henderson, NV 89014 USA
[7] Tempest Therapeut, San Francisco, CA 94104 USA
来源
CELL REPORTS | 2018年 / 25卷 / 11期
关键词
CANCER-THERAPY; PATHWAY; RESISTANCE; REGRESSION; RECEPTOR; POTENT; CGAS;
D O I
10.1016/j.celrep.2018.11.047
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8(+) effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNF alpha is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.
引用
收藏
页码:3074 / +
页数:17
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