TY - JOUR
T1 - PRAME as a potential target for immunotherapy in metastatic uveal melanoma
AU - Gezgin, Gülçin
AU - Luk, Sietse J.
AU - Cao, Jinfeng
AU - Dogrusöz, Mehmet
AU - Van Der Steen, Dirk M.
AU - Hagedoorn, Renate S.
AU - Krijgsman, Daniëlle
AU - Van Der Velden, Pieter A.
AU - Field, Matthew G.
AU - Luyten, Gregorius P.M.
AU - Szuhai, Karoly
AU - Harbour, J. William
AU - Jordanova, Ekaterina S.
AU - Heemskerk, Mirjam H.M.
AU - Jager, Martine J.
N1 - Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaophthalmol.2017.0729
DO - 10.1001/jamaophthalmol.2017.0729
M3 - Article
C2 - 28448663
AN - SCOPUS:85017676048
SN - 2168-6165
VL - 135
SP - 541
EP - 549
JO - JAMA Ophthalmology
JF - JAMA Ophthalmology
IS - 6
ER -