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 damage1. 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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This study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health (NIH) grants R35 CA197633 and P01 CA168585, the Ressler Family Fund, the Samuels Family Fund and the Garcia-Corsini Family Fund (to A.R.). Z.E. was supported in part by the Moffitt Cancer Center NCI Skin SPORE (5P50CA168536) and Moffitt’s Total Cancer Care Initiative and Collaborative Data Services (P30-CA076292) for this work. J.M.Z. is part of the UCLA Medical Scientist Training Program supported by NIH training grant GM08042. S.H.-L. was supported by a Young Investigator Award and a Career Development Award from the American Society of Clinical Oncology (ASCO), a Tower Cancer Research Foundation Grant, and a Dr. Charles Coltman Fellowship Award from the Hope Foundation. We acknowledge the Translational Pathology Core Laboratory (TPCL) and R. Guo, W. Li, J. Pang and M. H. Macabali from UCLA for blood and biopsy processing, and X. Li, L. Dong, J. Yoshizawa, and J. Zhou from the UCLA Clinical Microarray Core for sequencing expertise. G.V.L. is supported by an NHMRC Fellowship and The University of Sydney Medical Foundation. R.A.S. is supported by an NHMRC Fellowship.
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Cell Biology and Toxicology (2019)