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.

• Authors: Zeynep Eroglu, Jesse M Zaretsky, Siwen Hu-Lieskovan, Dae Won Kim, Alain Algazi, Douglas B Johnson, Elizabeth Liniker, Ben Kong, Rodrigo Munhoz, Suthee Rapisuwon, Pier Federico Gherardini, Bartosz Chmielowski, Xiaoyan Wang, I Peter Shintaku, Cody Wei, Jeffrey A Sosman, Richard W Joseph, Michael A Postow, Matteo S Carlino, Wen-Jen Hwu, Richard A Scolyer, Jane Messina, Alistair J Cochran, Georgina V Long, Antoni Ribas
• Journal: Nature (Nature) Vol. 553 Issue 7688 Pg. 347-350 (01 18 2018) ISSN: 1476-4687 [Electronic] England
• PMID: 29320474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Neurofibromin 1
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• B7-H1 Antigen (antagonists & inhibitors, metabolism)
• Biopsy
• CD8-Positive T-Lymphocytes (cytology, immunology)
• Cell Cycle Checkpoints
• Humans
• Immunotherapy
• Melanoma (genetics, immunology, metabolism, therapy)
• Mutation (genetics)
• Neurofibromin 1 (genetics)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Retrospective Studies