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OPINION

Alternative tumour-specific antigens

Nature Reviews Cancer volume 19, pages 465–478 (2019)Cite this article

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Abstract

The study of tumour-specific antigens (TSAs) as targets for antitumour therapies has accelerated within the past decade. The most commonly studied class of TSAs are those derived from non-synonymous single-nucleotide variants (SNVs), or SNV neoantigens. However, to increase the repertoire of available therapeutic TSA targets, ‘alternative TSAs’, defined here as high-specificity tumour antigens arising from non-SNV genomic sources, have recently been evaluated. Among these alternative TSAs are antigens derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other processes. Unlike the patient-specific nature of SNV neoantigens, some alternative TSAs may have the advantage of being widely shared by multiple tumours, allowing for universal, off-the-shelf therapies. In this Opinion article, we will outline the biology, available computational tools, preclinical and/or clinical studies and relevant cancers for each alternative TSA class, as well as discuss both current challenges preventing the therapeutic application of alternative TSAs and potential solutions to aid in their clinical translation.

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Fig. 1: Summary of tumour-specific antigen production in the tumour cell.
Fig. 2: Average tumour-specific antigen counts by cancer type.
Fig. 3: Computational workflow for tumour-specific antigen calling.

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Acknowledgements

This work was supported by the US National Institutes of Health grants F30 CA225136 (to C.C.S.), U54 CA198999 (to J.S.S.) and P50 CA058223 (to J.S.S.), as well as by a grant from the UNC University Cancer Research Fund (to B.G.V.) and a Susan G. Komen Career Catalyst Research Grant (to B.G.V.).

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Author notes

  1. These authors contributed equally: Benjamin G. Vincent, Jonathan S. Serody

Authors and Affiliations

  1. Department of Microbiology and Immunology, UNC School of Medicine, Marsico Hall, Chapel Hill, NC, USA

    Christof C. Smith, Shengjie Chai, Benjamin G. Vincent & Jonathan S. Serody

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Christof C. Smith, Sara R. Selitsky, Shengjie Chai, Paul M. Armistead, Benjamin G. Vincent & Jonathan S. Serody

  3. Lineberger Bioinformatics Core, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Marsico Hall, Chapel Hill, NC, USA

    Sara R. Selitsky

  4. Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Shengjie Chai & Benjamin G. Vincent

  5. Division of Hematology/Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Paul M. Armistead, Benjamin G. Vincent & Jonathan S. Serody

  6. Program in Computational Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Benjamin G. Vincent & Jonathan S. Serody

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Contributions

C.C.S., S.C., S.R.S. and P.M.A. researched the data for the article. All authors provided substantial contributions to discussion of the content. C.C.S. and P.M.A. wrote the article, and C.C.S. generated figures. All authors contributed to the review and editing of the manuscript prior to submission.

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Supplementary information

Glossary

Apheresis

Medical technique used to purify various components of whole blood. Apheresis can be performed to harvest purified T lymphocytes for subsequent immunotherapeutic application.

Artificial neural networks

A class of computational modelling based on biological neural networks, able to implement change based on training input and output information to form an optimized prediction model.

Binding core

The segment of polypeptide on an antigenic peptide responsible for interaction with the major histocompatibility complex binding groove. The binding core is recognized as an important predictor for binding affinity, but binding is also influenced by other factors of the epitope sequence.

Cancer–testis antigens

Antigens whose expression is limited to cancer cells and reproductive tissues but not adult somatic tissue.

Cytogenic response

A decrease in the number of cells with a particular chromosomal trait (classically associated with the BCR–ABL gene fusion) in response to therapy.

Doublet decoding

Translational process by which an amino acid is translated from a two-base-pair codon rather than the conventional three-base-pair codon. This process can result in -1 frameshifting during translation.

Epitope

Specific portion of the antigen specifically recognized by a T or B cell receptor.

HLA typing

Process for identifying the HLA receptor allele of a particular tissue. This can be performed through a variety of molecular or immunological techniques.

Immunogenomic analysis

Study of the combined genomics of the cancer cell and immune cell components of a tumour.

Insertion or deletion

(INDEL). Insertion of bases into or deletion of them from the genome of an organism, typically in the context of a mutation or genetic variation.

KD

Dissociation constant that measures the concentration of a ligand necessary to reversibly bind half of its corresponding molecular pair. In the context of peptide–major histocompatibility complex (MHC) binding, this refers to the concentration of peptide necessary to bind half of all MHC molecules.

Lynch syndrome

Also known as hereditary nonpolyposis colorectal cancer. An autosomal-dominant genetic disorder of DNA mismatch repair, resulting in increased risk of microsatellite instability-driven colon cancer (among other cancer types).

Myelodysplastic syndrome

A class of low-grade malignancies in which abnormal bone marrow stem cells fail to fully mature.

Negative selection

Process by which self-reactive T lymphocytes are deleted during T cell education in the thymus.

Neoantigens

Antigens specific to the genome of the cancer cell.

Nonsense-mediated decay

Checkpoint by which mRNA transcripts containing premature stop codons are eliminated in order to reduce aberrant translation.

Post-translational splicing

Post-translational excision of polypeptides, with subsequent ligation of the carboxy- and amino-terminal residues.

Predicted neoantigens

Genomically predicted neoantigens with unconfirmed tumour expression and/or in vivo immunogenicity.

Quantitative trait loci

Sections of DNA (loci) that are correlated with particular qualitative traits (or phenotypes) in an organismal population.

Retroelements

Genetic elements capable of self-amplification, found within the genome of eukaryotic organisms. Retrotransposon DNA can be transcribed into RNA, converted back into identical DNA via reverse transcription, and then inserted into the genome at particular target sites. Retroelements include retrotransposons and endogenous retroviruses.

Retrotransposons

A subset of retroelement in eukaryotic cells that possesses some characteristics of retroviruses and transposes through an RNA intermediary.

Ribosomal frameshifting

Process by which codons are translated in an out-of-frame manner via slippage of the ribosome into a +/- 1 or 2 base-pair position.

Segmental duplications

Long segments of repeated DNA (1-400 kb) with highly conserved sequences (>90%) that exist in the genome as a result of duplication events.

Spliceosome

Molecular machinery responsible for removal (splicing) of introns from pre-mRNA.

Tandem mass spectrometry

Multiple-step mass spectrometry (MS), whereby the sample is first ionized for separation in the first MS stage, followed by fragmentation for separation in the second MS stage.

Translocation breakpoints

Locations where two fragments of chromosome(s) are joined subsequent to chromosomal translocation.

Tumour antigens

Any antigen produced by the tumour cell, typically in the setting of enriched or specific expression relative to normal tissue(s).

Tumour-associated antigens

Antigens whose expression is enriched (but not specific) to cancer cells.

Tumour-specific antigens

(TSAs). Antigens (molecules capable of promoting an adaptive immune response) expressed by the tumour with minimal to no expression in normal tissue.

Viral-derived cancer antigens

Antigens expressed by cancer cells derived from an oncogenic viral origin.

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Smith, C.C., Selitsky, S.R., Chai, S. et al. Alternative tumour-specific antigens. Nat Rev Cancer 19, 465–478 (2019). https://doi.org/10.1038/s41568-019-0162-4

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