The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

被引：180

作者：

Freed-Pastor, William ^{[1
,2
]}

Lambert, Laurens ^{[1
,3
]}

Ely, Zackery ^{[1
,3
]}

Pattada, Nimisha ^{[1
]}

Bhutkar, Arjun ^{[1
]}

Eng, George ^{[1
,4
]}

Mercer, Kim ^{[1
]}

Garcia, Ana ^{[1
]}

Lin, Lin ^{[1
]}

Rideout, William, III ^{[1
]}

Hwang, William ^{[1
,5
,6
]}

Schenkel, Jason ^{[1
,7
]}

Jaeger, Alex ^{[1
]}

Bronson, Roderick ^{[1
]}

Westcott, Peter ^{[1
]}

Hether, Tyler ^{[8
]}

Divakar, Prajan ^{[8
]}

Reeves, Jason ^{[8
]}

Deshpande, Vikram ^{[4
]}

Delorey, Toni ^{[6
]}

Phillips, Devan ^{[6
]}

Yilmaz, Omer ^{[1
,3
,4
]}

Regev, Aviv ^{[1
,3
,6
,9
]}

Jacks, Tyler ^{[1
,3
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[2] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[3] MIT, Dept Biol, Cambridge, MA 02139 USA

[4] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[5] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA

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

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[8] NanoString Inc, Seattle, WA 98109 USA

[9] Genentech Inc, 1 DNA Way, San Francisco, CA USA

来源：

CANCER CELL | 2021年 / 39卷 / 10期

关键词：

T-CELL IMMUNITY; CTLA-4; BLOCKADE; RECEPTOR; TIGIT; IMMUNOGENICITY; IMMUNOTHERAPY; HETEROGENEITY; DYSFUNCTION; XENOGRAFTS; ACTIVATION;

D O I：

10.1016/j.ccell.2021.07.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8(+) T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

引用

页码：1342 / +

页数：33

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