Resistance to checkpoint blockade therapy through inactivation of antigen presentation

被引：731

作者：

Sade-Feldman, Moshe ^{[1
,2
]}

Jiao, Yunxin J. ^{[2
,3
]}

Chen, Jonathan H. ^{[2
,4
]}

Rooney, Michael S. ^{[2
]}

Barzily-Rokni, Michal ^{[1
]}

Eliane, Jean-Pierre ^{[4
]}

Bjorgaard, Stacey L. ^{[1
,2
]}

Hammond, Marc R. ^{[1
]}

Vitzthum, Hans ^{[1
]}

Blackmon, Shauna M. ^{[1
]}

Frederick, Dennie T. ^{[1
]}

Hazar-Rethinam, Mehlika ^{[1
]}

Nadres, Brandon A. ^{[1
]}

Van Seventer, Emily E. ^{[1
]}

Shukla, Sachet A. ^{[2
,5
]}

Yizhak, Keren ^{[2
]}

Ray, John P. ^{[2
]}

Rosebrock, Daniel ^{[2
]}

Livitz, Dimitri ^{[2
]}

Adalsteinsson, Viktor ^{[2
]}

Getz, Gad ^{[2
,4
]}

Duncan, Lyn M. ^{[4
]}

Li, Bo ^{[6
]}

Corcoran, Ryan B. ^{[1
]}

Lawrence, Donald P. ^{[1
]}

Stemmer-Rachamimov, Anat ^{[4
]}

Boland, Genevieve M. ^{[7
]}

Landau, Dan A. ^{[2
,8
,9
,10
]}

Flaherty, Keith T. ^{[1
]}

Sullivan, Ryan J. ^{[1
]}

Hacohen, Nir ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA

[2] Broad Inst Massachusetts Inst Technol MIT & Harva, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

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

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

[6] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[7] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[8] NYC, New York Genome Ctr, New York, NY 10013 USA

[9] NYC, Weill Cornell Med, Dept Med, New York, NY 10065 USA

[10] NYC, Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

美国国家科学基金会;

关键词：

CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; CTLA-4; BLOCKADE; PD-1; MUTATIONS; TUMORS; PEMBROLIZUMAB; GENOMICS; PLATFORM;

D O I：

10.1038/s41467-017-01062-w

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：

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (similar to 30%) compared to responders (similar to 10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

引用

页数：11

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