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High response rate to PD-1 blockade in desmoplastic melanomas

2018; Nature Portfolio; Volume: 553; Issue: 7688 Linguagem: Inglês

10.1038/nature25187

1476-4687

Zeynep Eroglu, Jesse M. Zaretsky, Siwen Hu‐Lieskovan, Dae Won Kim, Alain P. Algazi, Douglas B. Johnson, Elizabeth Liniker, Benjamin Y. Kong, Rodrigo Ramella 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 L. Messina, Alistair J. Cochran, Georgina V. Long, Antoni Ribas,

Cutaneous Melanoma Detection and Management

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.