Transcriptional Mechanisms of Resistance to Anti-PD-1 Therapy

被引：65

作者：

Ascierto, Maria L. ^{[1
,2
]}

Makohon-Moore, Alvin ^{[3
,4
]}

Lipson, Evan J. ^{[1
,2
]}

Taube, Janis M. ^{[2
,5
,6
]}

McMiller, Tracee L. ^{[2
,7
]}

Berger, Alan E. ^{[2
,8
]}

Fan, Jinshui ^{[2
,8
]}

Kaunitz, Genevieve J. ^{[2
,5
]}

Cottrell, Tricia R. ^{[2
,6
]}

Kohutek, Zachary A. ^{[9
]}

Favorov, Alexander ^{[2
,10
,11
]}

Makarov, Vladimir ^{[4
,9
]}

Riaz, Nadeem ^{[4
,9
]}

Chan, Timothy A. ^{[4
,9
]}

Cope, Leslie ^{[2
,10
]}

Hruban, Ralph H. ^{[2
,6
,12
]}

Pardoll, Drew M. ^{[1
,2
]}

Taylor, Barry S. ^{[4
,13
,14
]}

Solit, David B. ^{[14
]}

Iacobuzio-Donahue, Christine A. ^{[3
,4
]}

Topalian, Suzanne L. ^{[2
,7
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[2] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[5] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Lowe Family Genom Core, Baltimore, MD USA

[9] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

[10] Johns Hopkins Univ, Sch Med, Oncol Bioinformat Core, Baltimore, MD USA

[11] Russian Acad Sci, Vavilov Inst Gen Genet, Lab Syst Biol & Computat Genet, Moscow, Russia

[12] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD USA

[13] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[14] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 12期

关键词：

IMMUNE CHECKPOINT BLOCKADE; LARGE GENE LISTS; PD-1; BLOCKADE; PANCREATIC-CANCER; LUNG-CANCER; MELANOMA; MUTATIONS; EVOLUTION; METASTASIS; EXPRESSION;

D O I：

10.1158/1078-0432.CCR-17-0270

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy. Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function. Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes. (C) 2017 AACR. See related commentary by Wilmott et al., p. 2921

引用

页码：3168 / 3180

页数：13

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