@article{f776ecc16b614794b5511c1d7cce37ba,
title = "Transcriptional mechanisms of resistance to anti-PD-1 therapy",
abstract = "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.",
author = "Ascierto, {Maria L.} and Alvin Makohon-Moore and Lipson, {Evan J.} and Taube, {Janis M.} and McMiller, {Tracee L.} and Berger, {Alan E.} and Jinshui Fan and Kaunitz, {Genevieve J.} and Cottrell, {Tricia R.} and Kohutek, {Zachary A.} and Alexander Favorov and Vladimir Makarov and Nadeem Riaz and Chan, {Timothy A.} and Leslie Cope and Hruban, {Ralph H.} and Pardoll, {Drew M.} and Taylor, {Barry S.} and Solit, {David B.} and Iacobuzio-Donahue, {Christine A.} and Topalian, {Suzanne L.}",
note = "Funding Information: S.L. Topalian reports receiving commercial research grants from Bristol-Myers Squibb, holds ownership interest (including patents) in Five Prime Therapeutics, is a consultant/advisory board member for Five Prime Therapeutics and GlaxoSmithKline, and is related to the coinventor of patents licensed to Bristol-Myers Squibb and Potenza Therapeutics; the family member is also a consultant/advisory board member for MedImmune, Merck, Pfizer, Potenza Therapeutics, and Sanofi. E.J. Lipson reports receiving commercial research grants from Genentech and Merck and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, and Merck. D.M. Pardoll reports receiving commercial research grants from and holds ownership interest (including patents) in Bristol-Myers Squibb. J.M. Taube reports receiving commercial research grants from Bristol-Myers Squibb and is a consultant/advisory board member for AstraZeneca, Bristol-Myers Squibb, and Merck. No potential conflicts of interest were disclosed by the other authors. The authors thank Haiying Xu, Aleksandra Ogurtsova, and George A. Crabill (Johns Hopkins University School of Medicine) and Rajya Kappagantula (Memorial Sloan Kettering Cancer Center) for technical assistance, Steven Hashagen (Indica Labs) for assistance with CD8 T-cell mapping, Annamalai Selvakumar (Memorial Sloan Kettering Cancer Center) for assisting with HLA genotyping, and Ludmila Danilova (Johns Hopkins) for advice on statistical analyses. This study was supported by the Melanoma Research Alliance (to C.A. Iacobuzio-Donahue and S.L. Topalian), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (to J.M. Taube, D.M. Pardoll, and S.L. Topalian), the Barney Family Foundation (to S.L. Topalian), Moving for Melanoma of Delaware (to S.L. Topalian), the Laverna Hahn Charitable Trust (to S.L. Topalian), the National Cancer Institute (R01 CA142779 to J.M. Taube, D.M. Pardoll, and S.L. Topalian; 5T32 CA193145 to T.R. Cottrell; R01 CA179991 to C.A. Iacobuzio-Donahue; P30-CA008748 to Memorial Sloan Kettering Cancer Center), the MSKCC TROT Fellowship (to A. Makohon-Moore), the Starr Cancer Consortium (to T.A. Chan), the Pershing Square Sohn Cancer Research Foundation (to T.A. Chan), the Immunogenomics and Precision Oncology Platform (to T.A. Chan), and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology (to D.B. Solit). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2017 AACR.",
year = "2017",
month = jun,
day = "15",
doi = "10.1158/1078-0432.CCR-17-0270",
language = "English (US)",
volume = "23",
pages = "3168--3180",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",
}