Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy

被引：61

作者：

Jiang, Liwei ^{[1
]}

Wang, Yi-Jun ^{[1
]}

Zhao, Jing ^{[1
]}

Uehara, Mayuko ^{[1
]}

Hou, Qingming ^{[1
,5
]}

Kasinath, Vivek ^{[1
]}

Ichimura, Takaharu ^{[2
]}

Banouni, Naima ^{[1
]}

Dai, Li ^{[1
]}

Li, Xiaofei ^{[1
]}

Greiner, Dale L. ^{[3
]}

Shultz, Leonard D. ^{[4
]}

Zhang, Xiaolong ^{[6
]}

Sun, Zhen-Yu Jim ^{[7
,10
]}

Curtin, Ian ^{[10
]}

Vangos, Nicholas E. ^{[10
]}

Yeoh, Zoe C. ^{[10
]}

Geffken, Ezekiel A. ^{[10
]}

Seo, Hyuk-Soo ^{[7
,10
]}

Liu, Ze-Xian ^{[6
]}

Heffron, Gregory J. ^{[7
]}

Shah, Khalid ^{[8
,9
,11
]}

Dhe-Paganon, Sirano ^{[7
,10
]}

Abdi, Reza ^{[1
,11
]}

机构：

[1] Harvard Med Sch, Transplantat Res Ctr, Brigham & Womens Hosp, Renal Div, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA

[3] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA

[4] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[5] Qingdao Univ, Inst Neuroregenerat & Neurorehabil, Qingdao 266071, Peoples R China

[6] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou 510060, Peoples R China

[7] Harvard Med Sch, Blavatnik Inst, Dept Biol Chem & Mol Pharmacol, 240 Longwood Ave, Boston, MA 02115 USA

[8] Harvard Med Sch, Ctr Stem Cell Therapeut & Imaging, Brigham & Womens Hosp, Boston, MA 02115 USA

[9] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[10] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[11] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

来源：

CELL | 2020年 / 183卷 / 05期

关键词：

antitumor immune response; cancer-associated fibroblasts; granzyme B; SerpinB9;

D O I：

10.1016/j.cell.2020.10.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.

引用

页码：1219 / +

页数：33

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