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.

Eroglu, Z., Zaretsky, J.m., Hu-Lieskovan, S., Kim, D.w., Algazi, A., Johnson, D.b., et al. (2018). High response rate to PD-1 blockade in desmoplastic melanomas. NATURE, 553(7688), 347-350 [10.1038/nature25187].

High response rate to PD-1 blockade in desmoplastic melanomas

Gherardini, Pier Federico;
2018-01-18

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(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.
18-gen-2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Eroglu, Z., Zaretsky, J.m., Hu-Lieskovan, S., Kim, D.w., Algazi, A., Johnson, D.b., et al. (2018). High response rate to PD-1 blockade in desmoplastic melanomas. NATURE, 553(7688), 347-350 [10.1038/nature25187].
Eroglu, Z; Zaretsky, Jm; Hu-Lieskovan, S; Kim, Dw; Algazi, A; Johnson, Db; Liniker, E; Ben Kong, N; Munhoz, R; Rapisuwon, S; Gherardini, Pf; Chmielowski, B; Wang, X; Shintaku, Ip; Wei, C; Sosman, Ja; Joseph, Rw; Postow, Ma; Carlino, Ms; Hwu, W; Scolyer, Ra; Messina, J; Cochran, Aj; Long, Gv; Ribas, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/312295
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