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Defects in antigen processing and presentation: mechanisms, immune evasion and implications for cancer vaccine development

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Abstract

Human tumour cells express mutated and non-mutated proteins that can be processed and presented by these cells as peptides bound to human leukocyte antigen (HLA). Some of these peptides are recognized by cognate T cell receptors as ‘non-self’, leading to specific killing of tumour cells by T cells. This process is fundamental to the success of cancer immunotherapy, which exploits the ability of the immune system to eliminate transformed cells. Mutated antigens (neoantigens) have been implicated in the remarkable therapeutic efficacy of immune checkpoint inhibitors (ICIs), which boost endogenous antitumour immune responses. In recent years, the combination of ICIs with personalized cancer vaccines that target neoantigens and other tumour-specific antigens has emerged as a new therapeutic strategy. However, the robust immune pressure that ICIs exert on cancer cells inevitably amplifies the phenomenon of immune editing, which can allow cancer cells to develop resistance mechanisms that subvert surveillance by the immune system. Diminished antigenicity can be due to defects in the antigen processing and presentation machinery, such as HLA-I/II loss of heterozygosity and loss of functional β2-microglobulin. This poses a considerable challenge for combination therapies that include ICIs and for the design of cancer-specific vaccines.

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Fig. 1: Sources of tumour-specific antigens resulting from alterations in the genome, transcriptome, translatome, proteome and immunopeptidome.
Fig. 2: Overview of considerations for the optimal design of personalized cancer vaccines.

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Acknowledgements

This study was supported by the Ludwig Institute for Cancer Research, by grant no. KFS-5637-08-2022 from the Swiss Cancer Research Foundation (to M.B.-S.), the Swiss National Science Foundation PRIMA (grant no. PR00P3_193079 to M.B.-S.) and the Swiss Bridge Foundation Award (to M.B.-S.). The authors thank the members of the Immunopeptidomics Lab at the Department of Oncology, University Hospital of Lausanne, for their constructive discussions and valuable input.

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Authors and Affiliations

  1. Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland

    Florian Huber & Michal Bassani-Sternberg

  2. Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland

    Florian Huber & Michal Bassani-Sternberg

  3. AGORA Cancer Research Center, Lausanne, Switzerland

    Florian Huber & Michal Bassani-Sternberg

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  1. Florian Huber
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Correspondence to Michal Bassani-Sternberg.

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Glossary

Cancer-immunity cycle

The stepwise process in which tumour antigens are released, presented, recognized and lead to T cell-mediated killing, generating new antigens that restart the cycle.

Epitope spreading

The development of T cell reactivity to antigens distinct from those initially targeted by the vaccine.

Immune escape

The ability of tumour cells to avoid recognition and destruction by the immune system through mechanisms such as antigen loss, immune suppression or alteration of immune signalling pathways.

Immune landscapes

The overall composition and activation state of immune cells within a tumour or tissue microenvironment.

Immune pressure

The selective pressure exerted by the immune system that promotes the survival of resistant tumour clones.

Immune privileged

In the context of tumours, this refers to tumours that evade immune detection by lacking recognizable neoantigens, suppressing local immune responses or using mechanisms that inhibit T cell activation.

Immunopeptidome

The set of peptides displayed on cell-surface human leukocyte antigen (HLA) molecules.

Immunosurveillance

Continuous immune monitoring that detects and eliminates emerging malignant or infected cells.

Indels

Small insertions or deletions of nucleotides in DNA that can disrupt reading frames or alter protein sequence.

Shared tumour-associated antigens

Non-mutated proteins aberrantly expressed across many tumours that can be recognized by T cells.

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Huber, F., Bassani-Sternberg, M. Defects in antigen processing and presentation: mechanisms, immune evasion and implications for cancer vaccine development. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01208-8

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