Journal Article

DKFZ-2026-00071

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Systematic evaluation of neoepitope predictions challenges clinically observed T-cell responses and their impact on immune evasion.

Zaghla, B. K. Q. ; Safyürek, Z. ; Gröger, D. ; Mecklenbräuker, S. ; Lingstädt, N.-S. ; Popp, O. ; Spengler, J. ; Haji, M. ; Montesion, M. ; Albacker, L. A. ; Mertins, P. ; Klatt, M. G.DKFZ*

2026
BioMed Central London

Abstract: Peptide presentation on human leukocyte antigens (HLAs) is essential for initiating T-cell responses and all consequences of this presentation including anticancer immunity or immune escape. Many studies have relied on in silico prediction tools rather than biological measurement of HLA presentation to study these effects. To better assess the frequency and consequences of neoantigen presentation, we overexpressed 125 combinations of full-length neoantigens and one HLA class I allele to experimentally validate presentation of mutated and non-mutated HLA ligands through HLA ligand isolation followed by tandem mass spectrometry. A successful presentation was observed only in 22% of predicted cases with strong implications on previously described downstream effects. For example, the association of HLA loss of heterozygosity with predicted neoepitopes was challenged for 58% (73/125) of combinations. Furthermore, when testing 51 sequences used for personalized messenger RNA neoepitope vaccines, we observed that clinical responses were independent of the presentation status of the neoepitopes. Even a presumably neoepitope-specific and strongly expanded T cell receptor clone from a neoantigen vaccination study could not be linked to a successfully presented neoepitope. Overall, these data highlight the importance of validating the presentation of neoepitopes to fully understand our interpretation of clinical mutation-specific responses and their related effects, including immune evasion.

Keyword(s): Humans (MeSH) ; Immune Evasion (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Epitopes, T-Lymphocyte: immunology (MeSH) ; Antigens, Neoplasm: immunology (MeSH) ; Antigens, Neoplasm: genetics (MeSH) ; Antigen Presentation: immunology (MeSH) ; HLA Antigens: immunology (MeSH) ; HLA Antigens: genetics (MeSH) ; Cancer Vaccines: immunology (MeSH) ; Histocompatibility Antigens Class I: immunology (MeSH) ; Histocompatibility Antigens Class I: genetics (MeSH) ; Human leukocyte antigen - HLA ; Immunotherapy ; T cell Receptor - TCR ; Vaccine ; Epitopes, T-Lymphocyte ; Antigens, Neoplasm ; HLA Antigens ; Cancer Vaccines ; Histocompatibility Antigens Class I

Note: #DKTKZFB9#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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