{"doi":"10.1002/bco2.70037","title":"PRAME is not a frequently expressed antigen in renal cell carcinoma","abstract":"In patients with advanced renal cell carcinoma (RCC), immune checkpoint inhibitors (ICIs) have led to significant improvements in overall survival. However, not all patients respond to ICI-based regimens, and most patients that do will eventually develop resistance.1 This highlights the need for complementary and alternative immunotherapeutic strategies in RCC. Many newer strategies are tumour antigen targeted, such as antibody-drug conjugates, CAR T-cell therapy, T-cell receptor therapy and bispecific T-cell engagers.1 Such therapies have demonstrated promising anti-tumour activity in early-phase trials.1 The identification of targetable tumour-specific antigens is thus an important step for ICI-resistant RCC. Preferentially expressed antigen in melanoma (PRAME) is a protein classified under the cancer/testis antigen family. PRAME functions primarily as a repressor of retinoic acid signalling, preventing retinoic acid induced cell differentiation and proliferation arrest.2 It also contains multiple HLA-specific epitopes that can be presented by MHC class I molecules, activating CD8+ T cells.2 The normal expression of PRAME is limited to testes and ovarian cells, but it is pathologically expressed in numerous solid and haematological malignancies. For example, PRAME expression is observed in 88% of primary melanomas and 95% of metastatic melanomas, 80% of non-small cell lung cancers (NSCLCs) and 53% of breast cancers, among others.2 PRAME expression has been shown to be prognostic and is associated with advanced tumour stage and poor overall survival. The combination of PRAME's restricted cancer overexpression and immunomodulatory potential have made it a promising immunotherapeutic target. PRAME-targeting therapies have been in development for multiple malignancies using a variety of approaches, including bispecific T cell engagers, T-cell receptor adoptive cell therapies and antibody-drug conjugates. Ongoing trials include a Phase III trial testing a T cell receptor bispecific protein targeting PRAME and CD3 in melanoma (PRISM-MEL-301, NCT06112314) and Phase I/II trials enrolling PRAME-positive patients in multiple solid tumours.3, 4 Early results from these trials have demonstrated safety and anti-tumour activity in heavily pretreated patients across tumour types, including melanoma, ovarian cancer, head and neck cancer and synovial sarcoma.3, 4 PRAME expression patterns have not been thoroughly evaluated in RCC. A limited study found PRAME mRNA positivity in 15 of 39 (38%) RCC samples.5 A more systematic analysis of PRAME expression in epithelial tumours observed PRAME positivity by immunohistochemistry (IHC) in 20 of 175 clear cell RCC samples, with a 22% positivity rate in grade 3/4 samples versus 7% in grade 1/2 tumours.6 The purpose of this study was to comprehensively evaluate expression patterns of PRAME in RCC utilizing clinically annotated tissue microarrays (TMAs) of primary RCC tumours. We used an anti-PRAME antibody (clone EPR20330, Biocare) that is an FDA-approved in vitro diagnostic, typically used in CLIA-certified labs to aid in immunohistochemical melanoma diagnosis. We validated the specificity of this antibody in RCC via Western blotting using a panel of RCC cell lines and known positive and negative controls. From prior studies, the melanoma cell lines MP41 and YUKRIN served as positive controls, and human granulocyte cell lysate, HUVEC (human umbilical vein endothelial cells) and BxPC3 (pancreatic cancer) cells served as negative controls.7 Data from the Human Protein Atlas (HPA) was also used to identify five human RCC cell lines with differential PRAME mRNA expression (Figure 1A).8 We confirmed PRAME protein expression in these cell lines to be consistent with mRNA expression patterns from the HPA, with the highest levels of expression in Caki2 and A498 cells (Figure 1B). IHC for PRAME (1:100) was performed on three TMAs: one included 285 primary RCC tumours (169 clear cell, 34 papillary, 19 oncocytom","journal":"BJUI Compass","year":2025,"id":567264,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1471693,"name":"Yael Derdikman Ofir","orcid":null,"position":1,"is_corresponding":false},{"id":742933,"name":"Jacqueline E. Mann","orcid":null,"position":2,"is_corresponding":false},{"id":1166167,"name":"David Su","orcid":"0000-0002-8693-612X","position":3,"is_corresponding":false},{"id":1471694,"name":"Tara Kim","orcid":null,"position":4,"is_corresponding":false},{"id":1313259,"name":"Oscar Perales","orcid":"0000-0003-0800-4252","position":5,"is_corresponding":false},{"id":291533,"name":"Lin Zhang","orcid":"0000-0002-0418-5706","position":6,"is_corresponding":false},{"id":418428,"name":"Adebowale Adeniran","orcid":"0000-0001-9820-632X","position":7,"is_corresponding":false},{"id":226323,"name":"Harriet M. Kluger","orcid":"0000-0002-4932-9873","position":8,"is_corresponding":false},{"id":902967,"name":"David A. Schoenfeld","orcid":"0000-0002-5202-3744","position":9,"is_corresponding":false},{"id":639005,"name":"Irvin Yi","orcid":"0000-0003-4265-6334","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:56:44.340853Z","pmid":"40453487","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}