Immune checkpoint blockade, which blocks inhibitory signals of T cell activation, has shown tremendous success in treating cancer, although success still remains limited to a fraction of patients. To date, clinically effective CD8+ T cell responses appear to target predominantly antigens derived from tumour-specific mutations that accumulate in cancer, also called neoantigens. Tumour antigens are displayed on the surface of cells by class I human leukocyte antigens (HLA-I). To elicit an effective antitumour response, antigen presentation has to be successful at two distinct events: first, cancer antigens have to be taken up by dendritic cells (DCs) and cross-presented for CD8+ T cell priming. Second, the antigens have to be directly presented by the tumour for recognition by primed CD8+ T cells and killing. Tumours exploit multiple escape mechanisms to evade immune recognition at both of these steps. Here, we review the tumour-derived factors modulating DC function, and we summarize evidence of immune evasion by means of quantitative modulation or qualitative alteration of the antigen repertoire presented on tumours. These mechanisms include modulation of antigen expression, HLA-I surface levels, alterations in the antigen processing and presentation machinery in tumour cells. Lastly, as complete abrogation of antigen presentation can lead to natural killer (NK) cell-mediated tumour killing, we also discuss how tumours can harbour antigen presentation defects and still evade NK cell recognition.
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- Major histocompatibility complex
(MHC). A locus that encodes several genes involved in antigen presentation and other related immune processes.
- Human leukocyte antigen
(HLA). In humans, MHC is also called HLA. HLA-I, or MHC class-I, includes classical HLA-Ia genes (HLA-A, HLA-B and HLA-C) and non-classical HLA-Ib genes. Classical HLA genes present peptides at the cell surface, while non-classical HLA gene products have several other functions including natural killer cell activation or inhibition, and presentation of metabolites, lipids, etc. In this Review, we use HLA-I to refer to the classical genes only. Similarly, HLA-II will be used to refer to classical MHC class-II genes. For most of the discussion, we use the term HLA instead of MHC.
Mutated peptides presented on the tumour cell surface by HLA. They are specific to tumours, as they arise from somatic mutations, thus distinguishing them from self antigens.
- Professional antigen-presenting cells
(pAPCs). Cells that specialize in presenting antigens on MHC molecules to prime and stimulate T cells. These include dendritic cells, macrophages and B cells.
- Antigen processing and presentation machinery
(APM). Includes the peptide loading complex and also peptide processing machinery such as the proteasome.
- In situ vaccines
The delivery of an innate stimulus to dendritic cells (DCs) at the tumour site. Unlike conventional vaccines, which co-deliver antigens and innate stimulus to DCs to stimulate antitumour T cell immunity, in situ vaccines rely on the antigens released by dying tumour cells as a source of tumour antigens for DCs. Examples of innate stimuli evaluated in the clinic are TLR agonists (TLR7/8 ligands, TLR9 ligands, the TLR3 ligand poly(I:C)), STING agonist and anti-CD40 agonist antibody.
- Peptide loading complex
(PLC). Includes the core set of proteins in the endoplasmic reticulum (ER) that mediate peptide transport into the ER and subsequent loading of peptide onto HLA-I. These include TAP1, TAP2, tapasin, ERp57, calnexin, calreticulin, ERAP1, ERAP2, HLA-I and β2m.
- Polymorphism at the HLA locus
HLA is the most polymorphic locus in humans, with more than 19,000 alleles documented. HLA-I consists of three genes, and since both alleles of each gene are expressed, up to six different HLA-I proteins or allotypes may be expressed in an individual, with each allotype presenting its own set of peptides. As different HLA-I allotypes may present a distinct set of peptides, the total repertoire of peptides presented by HLA-I (also called the HLA-I ligandome) is highly diverse.
A catabolic pathway that degrades cytosolic components including proteins and organelles. Autophagosomes capture these cytosolic materials and fuse with lysosomes to mediate their degradation.
ERAP1 and ERAP2 are endoplasmic reticulum-resident aminopeptidases that may trim peptides that bind to HLA-I. ERAP1 and ERAP2 are collectively referred to as ERAP.
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Jhunjhunwala, S., Hammer, C. & Delamarre, L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer 21, 298–312 (2021). https://doi.org/10.1038/s41568-021-00339-z
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