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Review
. 2015:2015:948501.
doi: 10.1155/2015/948501. Epub 2015 Jun 16.

Human Tumor Antigens and Cancer Immunotherapy

Nathalie Vigneron  1
Affiliations
Review

Human Tumor Antigens and Cancer Immunotherapy

Nathalie Vigneron. Biomed Res Int. 2015.

Abstract

With the recent developments of adoptive T cell therapies and the use of new monoclonal antibodies against the immune checkpoints, immunotherapy is at a turning point. Key players for the success of these therapies are the cytolytic T lymphocytes, which are a subset of T cells able to recognize and kill tumor cells. Here, I review the nature of the antigenic peptides recognized by these T cells and the processes involved in their presentation. I discuss the importance of understanding how each antigenic peptide is processed in the context of immunotherapy and vaccine delivery.

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Figures

Figure 1
Figure 1
Tumor antigens recognized by cytolytic T lymphocytes. Tumor antigens are classified according to the pattern of expression of the parental gene. The production of antigenic peptides by cancer cells (upper panel) and healthy cells (lower panel) is depicted. Viral antigens are only expressed in virally infected cells. Mutated genes can give rise to a modified peptide that is able to bind the HLA class I molecules while the wild-type peptide cannot (left). The mutation can also alter a peptide, which is able to bind the HLA class I molecule, so that this modified peptide is now recognized as nonself by circulating CTL. Cancer-germline genes are expressed in tumors or germline cells as a result of whole genome demethylation. MAGE-type antigens encoded by cancer-germline genes are not expressed at the surface of healthy cells nor on germline cells since the latter do not express HLA class I molecules. Differentiation antigens are encoded by genes with a tissue-specific expression. They are therefore expressed by some types of tumors and the corresponding healthy tissue. Some genes are overexpressed in tumors as a result of increased transcription or gene amplification. The resulting peptides are highly expressed on these tumors but also show a low level of expression in some or all healthy tissues.
Figure 2
Figure 2
Processing of tumor antigens recognized by CD8+ T cells. CTL recognize peptides that are produced by the degradation of cellular proteins by the proteasome. Four types of proteasome exist, two of which are represented here (standard proteasome and immunoproteasome). Peptides resulting from proteasome degradation are then transported in the lumen of the ER by the TAP transporter. Peptides bearing an extended N-terminus can be further trimmed by additional proteases such as ERAP1 before being loaded on HLA class I molecules with the help of the peptide loading complex, which is composed of TAP, tapasin (Tpn), the oxidoreductase ERp57, and the chaperone calreticulin (CRT). Peptide/HLA complexes are then transferred to the cell surface through the secretory pathway.
Figure 3
Figure 3
Proteasome activities. (a) Peptide-bond hydrolysis. In the course of peptide-bond hydrolysis, the hydroxyl group of the N-terminal threonine produces a nucleophile attack on the carbonyl of the peptide bond. This leads to the formation of an acyl-enzyme intermediate in which a peptide fragment remains attached to the proteasome through an ester link. Finally hydrolysis of the acyl-enzyme intermediate by a water molecule present in the proteasome chamber will restore the hydroxyl group of the catalytic threonine and release the peptide. (b) Peptide splicing by the proteasome. Splicing of the antigenic peptide RTK_QLYPEW derived from the differentiation antigen gp100. After formation of the acyl-enzyme intermediate involving the fragment RTK, the free N-terminal amino-group of peptide QLYPEW present in the proteasome chamber performs a nucleophilic attack on the acyl-enzyme intermediate. This leads to the creation of a new peptide bond, which assembles both fragments of the spliced peptide. Balls represent the catalytic β subunits of the proteasome. The hydroxyl group of the N-terminal threonine is indicated.
Figure 4
Figure 4
Proteasome subtypes. Mammalian 20S proteasomes are composed four stacked rings of seven subunits each. The two outer rings are made of α-subunits and delimit the entrance of the catalytic chamber. The two inner rings are made of β subunits, three of which (β1, β2, and β5) are catalytically active. In immune cells or upon induction with IFNγ, catalytic subunits β1, β2, and β5 are replaced with their inducible counterparts β1i, β2i, and β5i to form immunoproteasomes. Besides standard and immunoproteasomes, two additional forms of proteasome exist, which contain a mixture of standard and immune catalytic subunits, as indicated. The processing ability of these four types of proteasomes was studied for the indicated peptides (lower part of the figure). ++: efficiently produced, +/−: slightly produced, and −: not produced.
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