Deregulation of HLA-I in cancer and its central importance for immunotherapy

It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applie...

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Bibliographic Details
Published in:Journal for immunotherapy of cancer 2021-08, Vol.9 (8), p.e002899
Main Authors: Hazini, Ahmet, Fisher, Kerry, Seymour, Len
Format: Article
Language:English
Subjects:
Animals
Antigen presentation
Autophagy
Binding sites
Cancer
Chromosomes
Cytotoxicity
Endoplasmic reticulum
Epigenetics
Genes
Haplotypes
HLA Antigens - immunology
Humans
Immunotherapy
Immunotherapy - methods
Lymphocytes
Mice
Mutation
Neoplasms - immunology
Peptides
Proteins
Review
T-Lymphocytes - immunology
Tumors
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Summary:It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applies selective pressure by eliminating tumor cells expressing antigens that are recognized by T cells. It is becoming increasingly clear that the same selective pressure may also select for tumor cells that evade immune detection by acquiring deficiencies in their human leucocyte antigen (HLA) presentation pathways, allowing important tumor antigens to persist within cells undetected by the immune system. Deficiencies in antigen presentation pathway can arise by a variety of mechanisms, including genetic and epigenetic changes, and functional antigen presentation is a hard phenomenon to assess using our standard analytical techniques. Nevertheless, it is likely to have profound clinical significance and could well define whether an individual patient will respond to a particular type of therapy or not. In this review we consider the mechanisms by which HLA function may be lost in clinical disease, we assess the implications for current immunotherapy approaches using checkpoint inhibitors and examine the prognostic impact of HLA loss demonstrated in clinical trials so far. Finally, we propose strategies that might be explored for possible patient stratification.
ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2021-002899