Abstract
PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.
Major finding: PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.
Mechanism: Desmoplastic melanomas have increased PD-L1 levels and T-cell infiltration at the invasive tumor margin.
Impact: PD-1 blockade may be more effective in patients with desmoplastic melanoma compared with other subtypes.
Desmoplastic melanoma is a rare chemotherapy-resistant melanoma subtype characterized by a dense collagenous stroma. These tumors commonly have a high mutational burden due to ultraviolet light–induced DNA damage, prompting Eroglu, Zaretsky, Hu-Lieskovan, and colleagues to hypothesize that these tumors might respond well to immune checkpoint blockade with anti–PD-1 or anti–PD-L1 antibodies. A retrospective analysis of pathology reports from 1,058 patients with advanced melanoma treated with anti–PD-1 or anti–PD-L1 antibodies identified 60 patients with advanced, unresectable desmoplastic melanoma. Patients with desmoplastic melanoma had a high response rate to PD-1 blockade. Overall, 42 of the 60 (70%) patients with desmoplastic melanoma had an objective response, including 19 (32%) complete responses and 23 (38%) partial responses. Whole-exome sequencing data from 17 patients revealed driving NF1 mutations in 14 of 17 samples (82.4%) and enrichment of loss-of-function mutations in TP53 and ARID2. However, these mutations were not associated with response to PD-1 blockade. In 19 available desmoplastic melanoma pretreatment biopsies (7 with overall responses and 6 with progressive disease), there was an increase in PD-L1 positive cells in the tumor parenchyma compared with non-desmoplastic melanoma, and this elevated PD-L1 expression was associated with an increased density of CD8+ T cells at the tumor invasive margin. The T-cell infiltration at the invasive edge of desmoplastic melanomas along with the increase in PD-L1–positive cells may explain the enhanced efficacy of PD-1 blockade compared with other melanoma subtypes. Collectively, these findings suggest that, despite the dense fibrous stroma that had been expected to limit immune infiltration, PD-1/PD-L1 blockade may be effective in patients with desmoplastic melanoma, supporting further clinical investigation of immune checkpoint blockade in these patients.
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