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Nature. 2018 Jan 18;553(7688):347-350. doi: 10.1038/nature25187. Epub 2018 Jan 10.

High response rate to PD-1 blockade in desmoplastic melanomas.

Author information

1
University of California Los Angeles, Los Angeles, California, USA.
2
Moffitt Cancer Center and University of South Florida, Tampa, Florida, USA.
3
The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA.
4
University of California San Francisco, San Francisco, California, USA.
5
Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA.
6
Melanoma Institute Australia, Sydney, New South Wales, Australia.
7
Westmead Hospital, Sydney, New South Wales, Australia.
8
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Weill Cornell Medical College, New York, New York, USA.
10
Georgetown Lombardi Cancer Center, Washington DC, USA.
11
Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
12
Mayo Clinic, Jacksonville, Florida, USA.
13
The University of Sydney, Sydney, New South Wales, Australia.
14
Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
15
Royal North Shore Hospital, Sydney, New South Wales, Australia.

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.

PMID:
29320474
PMCID:
PMC5773412
DOI:
10.1038/nature25187
[Indexed for MEDLINE]
Free PMC Article

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