Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

被引：2307

作者：

McGranahan, Nicholas ^{[1
,2
,3
]}

Furness, Andrew J. S. ^{[3
,4
]}

Rosenthal, Rachel ^{[3
]}

Ramskov, Sofie ^{[5
]}

Lyngaa, Rikke ^{[5
]}

Saini, Sunil Kumar ^{[5
]}

Jamal-Hanjani, Mariam ^{[3
]}

Wilson, Gareth A. ^{[1
,3
]}

Birkbak, Nicolai J. ^{[1
,3
]}

Hiley, Crispin T. ^{[1
,3
]}

Watkins, Thomas B. K. ^{[1
,3
]}

Shafi, Seema ^{[3
]}

Murugaesu, Nirupa ^{[3
]}

Mitter, Richard ^{[1
]}

Akarca, Ayse U. ^{[4
,6
]}

Linares, Joseph ^{[4
,6
]}

Marafioti, Teresa ^{[4
,6
]}

Henry, Jake Y. ^{[3
,4
]}

Van Allen, Eliezer M. ^{[7
,8
,9
]}

Miao, Diana ^{[7
,8
]}

Schilling, Bastian ^{[10
,11
]}

Schadendorf, Dirk ^{[10
,11
]}

Garraway, Levi A. ^{[7
,8
,9
]}

Makarov, Vladimir ^{[12
]}

Rizvi, Naiyer A. ^{[13
]}

Snyder, Alexandra ^{[14
,15
]}

Hellmann, Matthew D. ^{[14
,15
]}

Merghoub, Taha ^{[14
,16
]}

Wolchok, Jedd D. ^{[14
,15
,16
]}

Shukla, Sachet A. ^{[7
,8
]}

Wu, Catherine J. ^{[7
,8
,17
,18
]}

Peggs, Karl S. ^{[3
,4
]}

Chan, Timothy A. ^{[12
]}

Hadrup, Sine R. ^{[5
]}

Quezada, Sergio A. ^{[3
,4
]}

Swanton, Charles ^{[1
,3
]}

机构：

[1] Francis Crick Inst, London WC2A 3LY, England

[2] UCL, Ctr Math & Phys Life Sci & Expt Biol CoMPLEX, Mortimer St, London WC1E 6BT, England

[3] UCL Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London WC1E 6BT, England

[4] UCL, UCL Canc Inst, Canc Immunol Unit, Mortimer St, London WC1E 6BT, England

[5] Tech Univ Denmark, Natl Vet Inst, Sect Immunol & Vaccinol, DK-1970 Frederiksberg C, Denmark

[6] UCL, Dept Cellular Pathol, Mortimer St, London WC1E 6BT, England

[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

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

[9] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA

[10] Univ Duisburg Essen, Univ Hosp, Dept Dermatol, D-45147 Essen, Germany

[11] German Canc Consortium DKTK, D-69121 Heidelberg, Germany

[12] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[13] Columbia Univ, Hematol Oncol Div, 177 Ft Washington Ave, New York, NY 10032 USA

[14] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[15] Weill Cornell Med Coll, New York, NY 10065 USA

[16] Mem Sloan Kettering Canc Ctr, Ludwig Collaborat Lab, New York, NY 10065 USA

[17] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[18] Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA

来源：

SCIENCE | 2016年 / 351卷 / 6280期

基金：

欧洲研究理事会;

关键词：

ANALYSIS REVEALS; CTLA-4; BLOCKADE; CANCER;

D O I：

10.1126/science.aaf1490

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：

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.

引用

页码：1463 / 1469

页数：7

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