HLA‐DRB1 Allelic Combinations Differentially Shape Dendritic Cell Antigen Presentation Enhanced by Tumour Cell Line Lysate‐Pulsing

TL;DR

This study explores how different HLA-DRB1 allele combinations affect dendritic cell antigen presentation, especially when enhanced by tumor cell lysates, which could help in designing personalized cancer immunotherapies.

Contribution

The study reveals how HLA-DRB1 allelic combinations influence antigen presentation and how pulsing with tumor lysates modulates this process.

Findings

HLA-DR heterozygosity strongly influences peptide repertoires in an allele-specific manner.

Pulsing dendritic cells with MCF-7 lysates increased peptide overlap and identified 58 putative tumor-derived proteins.

Peptide presentation from tumor proteins reinforced allele-specific dominance patterns observed in the immunopeptidome.

Abstract

The anti‐tumour immune response plays a pivotal role in eliminating tumour cells, with the presence of tumour‐infiltrating lymphocytes (TILs) often correlated with improved patient outcomes. Among these, CD4+ T lymphocytes act as key orchestrators of the immune response, functioning as effector and regulatory cells, and are essential for establishing immunological memory. To better understand the role of CD4+ T cells in anti‐tumour immunity, we analysed the HLA‐II immunopeptidome of dendritic cells (DCs) from HLA‐heterozygous donors pulsed with a protein extract from the MCF‐7 tumour cell line. Our objective was to identify differences in the arrays of peptides binding distinct HLA‐DRB1 allele combinations and the effect of DC pulsing on peptide presentation. We found that presented peptide repertoires are strongly influenced by HLA‐DR heterozygosity in an allele‐specific manner. Alleles with high binding strength (e.g., DRB1*01:01, DRB1*03:01 and DRB1*04:04) tended to dominate peptide presentation; however, this dominance is significantly modulated by the allelic combination, suggesting that antigen presentation is shaped not only by individual allele properties but also by their combinations. Pulsing DCs with MCF‐7 extracts increased peptide overlap between donors and enabled the identification of 58 proteins putatively derived from the tumour cell line lysates. Interestingly, peptide presentation from these proteins reinforced allele‐specific features of dominance and weakness previously observed across the entire immunopeptidome. Gaining insights into the peptide repertoire presented by distinct HLA‐DR combinations could inform the design of personalised immunotherapies based on peptide‐pulsed DCs, ultimately enhancing CD4+ TIL responses across diverse patient populations.

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