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. 2024 Aug;485(2):335-346.
doi: 10.1007/s00428-024-03846-0. Epub 2024 Jun 18.

Expression of the tumor antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE in pediatric and adult melanoma: a retrospective case control study

Stephan Forchhammer  1 , Oltin Tiberiu Pop  2 , Matthias Hahn  3 , Valentin Aebischer  3 , Christian M Seitz  4 , Christopher Schroeder  5 , Alexandra Liebmann  5 , Michael Abele  4 , Hannah Wild  4 , Ewa Bien  6 , Michal Kunc  7 , Dominik T Schneider  8 , Katarina Cuk  9 , Isabel Büttel  9 , Carina Flemmig  9 , Magdalena Peters  9 , Mark Laible  9 , Patrick Brück  9 , Özlem Türeci  9 , Ugur Sahin  9 , Lukas Flatz  3   2   10 , Ines B Brecht  4
Affiliations

Expression of the tumor antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE in pediatric and adult melanoma: a retrospective case control study

Stephan Forchhammer et al. Virchows Arch. 2024 Aug.

Abstract

Tumor-associated antigens (TAAs) are potential targets for T cell-based immunotherapy approaches in cutaneous melanoma. BNT111, an investigational lipoplex-formulated mRNA-based therapeutic cancer vaccine encoding melanoma TAAs NY-ESO-1, tyrosinase, MAGE-A3, and TPTE, is undergoing clinical testing in adults. Expression of these TAAs in pediatric melanoma is unclear but is a prerequisite for feasibility of this treatment approach in children with melanoma. Our main objective was to characterize expression of those TAAs in pediatric melanomas compared to control cohorts. In this retrospective case control study, protein and transcript expression of NY-ESO-1, tyrosinase, MAGE-A3, and TPTE were analyzed in a cohort of 25 pediatric melanomas, 31 melanomas of young adults, 29 adult melanomas, and 30 benign melanocytic nevi in children using immunohistochemical staining and digital pathology (QuPath) and reverse transcription quantitative PCR. Based on IHC analysis, pediatric melanomas expressed tyrosinase (100.0%), TPTE (44.0%), MAGE-A3 (12.0%), and NY-ESO-1 (8.0%). Young adult melanomas expressed tyrosinase (96.8%), NY-ESO-1 (19.4%), MAGE-A3 (19.4%), and TPTE (3.2%). Adult melanomas expressed tyrosinase (86.2%), MAGE-A3 (75.9%), NY-ESO-1 (48.3%), and TPTE (48.3%). Childhood melanocytic nevi only expressed tyrosinase (93.3%). Expression prevalence of individual TAAs did not differ between subtypes of pediatric melanoma, and no association with prognosis was found. All four TAAs were expressed in pediatric melanoma, albeit NY-ESO-1 and MAGE-A3 to a lesser extent than in adult melanoma. These data support the possibility of investigating vaccines targeting these TAAs for the treatment of pediatric melanoma.

Keywords: Cancer vaccine; Pediatric melanoma; Prognostic factor; TAA.

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Conflict of interest statement

SF: SF received institutional funding from BioNTech SE in relation to the submitted work, received personal honoraria from Kyowa Kirin and Recordati Rare Diseases (speaker’s honoraria), as well as institutional grants from Neracare and SkylineDX outside the submitted work.

OTP: OTP has no conflict of interest to declare.

MH: MH has no conflict of interest to declare.

VA: VA has no conflict of interest to declare.

CMS: CMS has no conflict of interest to declare.

CS: CS reports institutional grants from Illumina and research grants from BMS Stiftung Immunonkologie and Westdeutsche Studiengruppe GmbH outside the submitted work.

AL: AL has no conflict of interest to declare.

MA: MA has no conflict of interest to declare.

HW: HW has no conflict of interest to declare.

EB: EB has no conflict of interest to declare.

MK: MK has no conflict of interest to declare.

DS: DS has no conflict of interest to declare.

KC: KC is an employee at BioNTech and holds securities from BioNTech SE.

IB: IB is an employee at BioNTech and holds securities from BioNTech SE.

CF: CF is an employee at BioNTech and holds securities from BioNTech SE.

MP: MP is an employee at BioNTech and holds securities from BioNTech SE.

ML: ML is an employee at BioNTech and holds securities from BioNTech SE.

PB: PB is an employee at BioNTech and holds securities from BioNTech SE.

ÖT: ÖT is co-founder, management board member, and employee at BioNTech. ÖT has a leadership role at the Helmholtz Institute HI-TRON Mainz and is a founding member of TRON Translational Oncology Mainz. ÖT holds a professorship at the Johannes Gutenberg University. ÖT is an inventor on patents and patent applications related to RNA technology. ÖT holds securities from BioNTech SE.

US: US is co-founder, management board member, and employee at BioNTech. US has a leadership role at the Helmholtz Institute HI-TRON Mainz and is a founding member of TRON Translational Oncology Mainz. He holds a professorship at the Johannes Gutenberg University as professor in 2022 and was awarded with German Future Prize 2021. US is an inventor on patents and patent applications related to RNA technology. US holds securities from BioNTech SE.

LF: LF has/had advisory roles for Novartis, Sanofi, Philogen, and Bristol-Myers Squibb. LF received research support by Hookipa Pharma, Mundipharma and the Novartis Foundation. All outside the submitted work.

IBB: IBB received institutional funding from BioNTech SE in relation to the submitted work. IBB had advisory roles for Alexion outside the submitted work.

Figures

Fig. 1
Fig. 1
Immunohistochemical staining of TAA protein expressions in pediatric melanomas. a Positive NY-ESO-1 staining of patient K5, b negative NY-ESO-1 staining of patient K1, c positive tyrosinase staining of patient K22, d negative tyrosinase staining of adult patient A20 as negative staining of tyrosinase is absent in our cohort of pediatric melanoma, e positive MAGE-A3 staining of patient K1, f negative MAGE-A3 staining of patient K5, g positive TPTE staining of patient K1, h negative TPTE staining of patient K27. Scale bars are equal to 50 µm
Fig. 2
Fig. 2
Expression levels of NY-ESO-1, tyrosinase, MAGE-A3, and TPTE a–d Protein expression by immunohistochemistry. a Pediatric melanoma, b melanoma in young adults, c adult melanoma, d benign nevi of childhood. e–h Transcript expression by RT-qPCR. e pediatric melanoma, f melanoma in young adults, g adult melanoma, h benign nevi of childhood. Samples with late or no Cqs for targets were classified as negative. i Concordance of IHC and RT-qPCR over all samples (n = 114). OPA overall percent agreement, PPA positive percent agreement, NPA negative percent agreement. j–m Protein expression of TAAs in different age strata and subtypes of pediatric melanoma. j Childhood melanoma defined as patients under 12 years, k adolescent melanoma defined as patients from 12 to 18 years, l Spitzoid melanoma, m non-spitzoid melanoma. CM conventional melanoma (includes SSM, NM, and ALM), CNM congenital nevus melanoma, MET metastasis, OT other type of melanoma
Fig. 3
Fig. 3
Expression of TAAs (IHC) in relation to patient age Samples were combined in age groups of 20 years: 0–20 (n = 27), 21–40 (n = 32), 41–60 (n = 7), 61–80 (n = 14), 81 + (n = 5). a, b NY-ESO-1, c, d tyrosinase, e, f MAGE-A3, g, h TPTE, a, c, e, g relative expression frequency per age group in pediatric, young adult, and primary adult melanomas, b, d, f, h logistic regression models over pediatric, young adult, and adult melanoma samples. p Values were determined with likelihood ratio G2 test
Fig. 4
Fig. 4
Event-free survival of melanoma patients stratified by TAA expression a, c, e, g Pediatric melanoma. As all pediatric melanomas were positive for tyrosine (c), an analysis was not possible. b, d, f, h Non-pediatric melanoma. a, b NY-ESO-1 expression; c, d tyrosinase expression; e, f MAGE-A3 expression; g, h TPTE expression
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