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

  • Author(s): Eroglu, Zeynep;
  • Zaretsky, Jesse M;
  • Hu-Lieskovan, Siwen;
  • Kim, Dae Won;
  • Algazi, Alain;
  • Johnson, Douglas B;
  • Liniker, Elizabeth;
  • Ben Kong;
  • Munhoz, Rodrigo;
  • Rapisuwon, Suthee;
  • Gherardini, Pier Federico;
  • Chmielowski, Bartosz;
  • Wang, Xiaoyan;
  • Shintaku, I Peter;
  • Wei, Cody;
  • Sosman, Jeffrey A;
  • Joseph, Richard W;
  • Postow, Michael A;
  • Carlino, Matteo S;
  • Hwu, Wen-Jen;
  • Scolyer, Richard A;
  • Messina, Jane;
  • Cochran, Alistair J;
  • Long, Georgina V;
  • Ribas, Antoni
  • et al.
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.

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