Last Licensed Non-Classical Peptide Presenter HLA-F: Its Occurrence, Immunoediting Significance, and Possible Therapeutic Implications in Renal Cell Carcinoma

Among non-classical human leukocyte antigen (HLA) molecules, HLA-F remains the most enigmatic. Its precise functions, including the recently described peptide-presenting capability, are still not fully understood. Renal cell carcinoma (RCC) is characterized by its resistance to radiotherapy and chemotherapy, and it is known for its immunogenicity. The prognostic significance of HLA-F expression in neoplastic cells has not been well defined. We evaluated HLA-F–specific mRNA transcripts in 73 RCC samples and 54 adjacent normal kidney parenchyma samples and statistically correlated the results with several clinicopathological parameters. Our analysis revealed that HLA-F is upregulated in RCC. Interestingly, higher HLA-F expression was associated with prolonged disease-free survival, more favorable pT stage, and lower WHO/ISUP grade. Given the potential for interferon-mediated aberrant activation of non-classical HLA molecules, assessment of HLA-F status could help identify RCC patients who might benefit from tailored neoadjuvant biological or immunological therapies. Overall, HLA-F may serve as a valuable prognostic biomarker in RCC, and further studies are warranted to elucidate its functional and clinical significance.