Journal
NATURE
Volume 553, Issue 7688, Pages 347-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature25187
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Funding
- Grimaldi Family Fund
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health (NIH) [R35 CA197633, P01 CA168585]
- Ressler Family Fund
- Samuels Family Fund
- Garcia-Corsini Family Fund
- Moffitt Cancer Center NCI Skin SPORE [5P50CA168536]
- Moffitt's Total Cancer Care Initiative and Collaborative Data Services [P30-CA076292]
- NIH training grant [GM08042]
- American Society of Clinical Oncology (ASCO)
- Tower Cancer Research Foundation Grant
- Dr. Charles Coltman Fellowship Award from the Hope Foundation
- NHMRC Fellowship
- University of Sydney Medical Foundation
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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(1). 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.
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