Functional Immunopeptidomics by Characterizing Immunopeptides Against HLAs, TCRs, and Antibodies.

Authors

Hongyi Liu, Effram Wei, Yingwei Hu, Yuefan Wang, Zhenyu Sun, Hui Zhang

Published in

Research square. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

Target-directed immunotherapies, including TCR-T cell therapies, targeted antibody therapy, and therapeutic vaccines, rely on the identification of tumor-specific antigens (TSAs). However, classical immunopeptidomics is severely constrained by an inability to distinguish passively presented self-ligands of HLAs from functionally recognized by T cells. To resolve these challenges, we developed immunopeptidomics for receptor-associated antigens, a platform capable of sequentially isolating immunopeptidome and their functions with immune cell receptors from a single clinical tissue specimen. Applied to a cohort of 30 renal cell carcinoma (RCC) specimens (18 primary tumors and 12 paired normal adjacent tissues), this approach generated expansive presentation maps encompassing 38,848 unique HLA-I and 26,961 unique HLA-II peptides. Functional receptor captures (IgG- and TCR-bound) achieved up to 5.3-fold higher tumor-specific peptide (TSP) purity ratios compared to direct baseline HLA isolation. Furthermore, cross-fractional co-identification validated recurrent, high-priority unmutated targets (NNMT, TMBIM6, RPL3, VIM, and ENPP3) alongside tumor-specific phosphopeptide hubs and macrophage-restricted N-glycopeptides (CD68). Integrating companion global proteomics uncovered a fundamental regulatory divergence between MHC classes: HLA-I presentation throughput scales linearly (R = 0.883) via a STAT1-orchestrated transcriptional program driving the antigen presentation machinery (APM), whereas HLA-II presentation is uncoupled from parental protein abundance (R = 0.302) due to asynchronous downstream endolysosomal processing and proteolytic over-cleavage kinetics. Together, this platform establishes a micro-input framework that unifies physical presentation with native functional characterization and microenvironmental regulation to accelerate target discovery in low-TMB human cancers.

PMID:
42926996
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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