Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

被引：128

作者：

Bailey, Peter ^{[1
]}

Chang, David K. ^{[1
,2
,3
,4
]}

Forget, Marie-Andree ^{[5
]}

San Lucas, Francis A. ^{[5
]}

Alvarez, Hector A.

Haymaker, Cara ^{[5
]}

Chattopadhyay, Chandrani ^{[5
]}

Kim, Sun-Hee ^{[5
]}

Ekmekcioglu, Suhendan ^{[5
]}

Grimm, Elizabeth A. ^{[5
]}

Biankin, Andrew V. ^{[1
,2
,3
,4
]}

Hwu, Patrick ^{[5
]}

Maitra, Anirban ^{[6
,7
]}

Roszik, Jason ^{[5
,8
]}

机构：

[1] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland

[2] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow G31 2ER, Lanark, Scotland

[3] Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW 2200, Australia

[4] Univ New South Wales, Fac Med, South Western Sydney Clin Sch, Liverpool, NSW 2170, Australia

[5] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Ahmed Ctr Pancreat Canc Res, Dept Pathol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Ahmed Ctr Pancreat Canc Res, Dept Translat Mol Pathol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, 1515 Holcombe Blvd, Houston, TX 77030 USA

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

英国惠康基金;

关键词：

RNA-SEQ DATA; NITRIC-OXIDE; CELLS; TRIAL; IMMUNOSUPPRESSION; IDENTIFICATION; EXPRESSION; INDUCTION; SYNTHASE; SURVIVAL;

D O I：

10.1038/srep35848

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：

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues.

引用

页数：8

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