High response rate to PD-1 blockade in desmoplastic melanomas Journal Article
| Authors: | Eroglu, Z.; Zaretsky, J. M.; Hu-Lieskovan, S.; Kim, D. W.; Algazi, A.; Johnson, D. B.; Liniker, E.; Kong, B.; Munhoz, R.; Rapisuwon, S.; Gherardini, P. F.; Chmielowski, B.; Wang, X.; Shintaku, I. P.; Wei, C.; Sosman, J. A.; Joseph, R. W.; Postow, M. A.; Carlino, M. S.; Hwu, W. J.; Scolyer, R. A.; Messina, J.; Cochran, A. J.; Long, G. V.; Ribas, A. |
| Article Title: | High response rate to PD-1 blockade in desmoplastic melanomas |
| Abstract: | Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; protein expression; aged; middle aged; human cell; major clinical study; advanced cancer; cd8 antigen; gene; ipilimumab; multiple cycle treatment; retrospective study; drug response; melanoma cell; stroma; desmoplastic melanoma; cancer tissue; adaptive immunity; programmed death 1 receptor; tumor invasion; nf1 gene; nivolumab; bms 936559; very elderly; human; male; female; priority journal; article; pembrolizumab; whole exome sequencing; mutational load |
| Journal Title: | Nature |
| Volume: | 553 |
| Issue: | 7688 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-01-18 |
| Start Page: | 347 |
| End Page: | 350 |
| Language: | English |
| DOI: | 10.1038/nature25187 |
| PROVIDER: | scopus |
| PMCID: | PMC5773412 |
| PUBMED: | 29320474 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2018 -- Source: Scopus |
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