PRAME as a potential target for immunotherapy in metastatic uveal melanoma

Gülçin Gezgin, Sietse J. Luk, Jinfeng Cao, Mehmet Dogrusöz, Dirk M. Van Der Steen, Renate S. Hagedoorn, Daniëlle Krijgsman, Pieter A. Van Der Velden, Matthew G. Field, Gregorius P.M. Luyten, Karoly Szuhai, J. William Harbour, Ekaterina S. Jordanova, Mirjam H.M. Heemskerk, Martine J. Jager

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


IMPORTANCE: Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy. OBJECTIVE: To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM. DESIGN, SETTING, AND PARTICIPANTS: An experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining. MAIN OUTCOMES AND MEASURES: Interferon γ production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM. RESULTS: Of the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P =.005), ciliary body involvement (59% vs 26%; P =.008), and amplification of chromosome8q (66%vs 23%; P =.002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNAin 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I. CONCLUSIONS AND RELEVANCE: PRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.

Original languageEnglish (US)
Pages (from-to)541-549
Number of pages9
JournalJAMA Ophthalmology
Issue number6
StatePublished - Jun 2017
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology


Dive into the research topics of 'PRAME as a potential target for immunotherapy in metastatic uveal melanoma'. Together they form a unique fingerprint.

Cite this