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  • Review Article
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Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire

Nature Reviews Clinical Oncology volume 17, pages 595–610 (2020)Cite this article

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Abstract

Immune-checkpoint inhibition provides an unmatched level of durable clinical efficacy in various malignancies. Such therapies promote the activation of antigen-specific T cells, although the precise targets of these T cells remain unknown. Exploiting these targets holds great potential to amplify responses to treatment, such as by combining immune-checkpoint inhibition with therapeutic vaccination or other antigen-directed treatments. In this scenario, the pivotal hurdle remains the definition of valid HLA-restricted tumour antigens, which requires several levels of evidence before targets can be established with sufficient confidence. Suitable antigens might include tumour-specific antigens with alternative or wild-type sequences, tumour-associated antigens and cryptic antigens that exceed exome boundaries. Comprehensive antigen classification is required to enable future clinical development and the definition of innovative treatment strategies. Furthermore, clinical development remains challenging with regard to drug manufacturing and regulation, as well as treatment feasibility. Despite these challenges, treatments based on diligently curated antigens combined with a suitable therapeutic platform have the potential to enable optimal antitumour efficacy in patients, either as monotherapies or in combination with other established immunotherapies. In this Review, we summarize the current state-of-the-art approaches for the identification of candidate tumour antigens and provide a structured terminology based on their underlying characteristics.

Key points

  • Immune-checkpoint inhibition has profoundly changed the paradigm for the care of several malignancies. Although these therapies activate antigen-specific T cells, the precise mechanisms of action and their specific targets remain largely unknown.

  • Anticancer immunotherapies encompass two fundamentally different therapeutic principles based on knowledge of their therapeutic targets, that either have been characterized (antigen-aware) or have remained elusive (antigen-unaware).

  • HLA-presented tumour antigens of potential therapeutic relevance can comprise alternative or wild-type amino acid sequences and can be subdivided into different categories based on their mechanisms of formation.

  • The available methods for the detection of HLA-presented antigens come with intrinsic challenges and limitations and, therefore, warrant multiple lines of evidence of robust tumour specificity before being considered for clinical use.

  • Knowledge obtained using various antigen-detection strategies can be combined with different therapeutic platforms to create individualized therapies that hold great promise, including when combined with already established immunotherapies.

  • Tailoring immunotherapies while taking into account the substantial heterogeneity of malignancies as well as that of HLA loci not only requires innovative science, but also demands innovative approaches to trial design and drug regulation.

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Fig. 1: Adjustment of patient-adapted and tumour-directed drug products and therapies for clinical use.
Fig. 2: Cancer-related cellular alterations and characterization of HLA-presented tumour-specific and tumour-associated peptides.
Fig. 3: Current levels of scientific evidence for discovery and characterization of different classes of MHC-presented antigens.
Fig. 4: Antigen identification and selection for patient-adapted therapy.

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Acknowledgements

The authors thank L. Yakes from the Department of Immunology at the University of Tübingen for language editing and editorial assistance, and A. Marcu from the Department of Immunology at the University of Tübingen for helpful discussions.

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Author notes

  1. These authors contributed equally: Sebastian P. Haen, Markus W. Löffler

Authors and Affiliations

  1. Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany

    Sebastian P. Haen, Markus W. Löffler & Hans-Georg Rammensee

  2. Department of Oncology, Haematology and Bone Marrow Transplantation with the Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Sebastian P. Haen

  3. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Partner Site Tübingen, Tübingen, Germany

    Sebastian P. Haen, Markus W. Löffler & Hans-Georg Rammensee

  4. Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany

    Markus W. Löffler & Hans-Georg Rammensee

  5. Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany

    Markus W. Löffler

  6. Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany

    Markus W. Löffler

  7. Department of Oncology, Haematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, Bonn, Germany

    Peter Brossart

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Correspondence to Sebastian P. Haen.

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Competing interests

S.P.H. has acted as an advisory board member for Abbvie, Bristol–Myers Squibb, MSD and Roche, and is a co-inventor of several patents owned by Immatics Biotechnologies. M.W.L. is a co-inventor of several patents owned by Immatics Biotechnologies, and has acted as a consultant and/or advisory board member for Boehringer Ingelheim. H.-G.R. has ownership interest (including shares) in CureVac, Immatics Biotechnologies and Synimmune, is a co-inventor and/or has shared interests in several patents held by CureVac, Immatics Biotechnologies and Synimmune, and is a co-inventor and shares the patent for the adjuvant candidate XS15. P.B. has acted as a consultant or advisory board member for Amgen, AstraZeneca, Bristol–Myers Squibb, MSD and Roche, has received speaker’s fees from Abbvie, AstraZeneca, Bristol-Myers Squibb, and MSD, and has ownership interests in Immatics Biotechnologies.

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Related links

HLA Alleles: http://hla.alleles.org/alleles

Glossary

Antigens

Immunologically recognizable cell-surface structures.

Antigen-aware therapy

(AaT). An active immunotherapy leading to the activation of and/or constituting antigen-specific cells designed to target known and/or well-defined antigens.

Antigen-unaware therapy

(AuT). An active immunotherapy leading to the activation of and/or constituting antigen-specific cells designed to targeting uncharacterized antigens.

Cell-surface antigens

Proteins or parts thereof located on the outer side of the cell membrane that are therefore accessible from outside the cell.

T cell repertoire

The fraction of T cells capable of reacting against a defined HLA-restricted antigen, as detected by assays designed to measure immune cell function, without confirmation of lytic activity.

Uniquely assembled drug product

(UADP). Drug product, or set of drug products assembled and (pre-)manufactured individually that can then be assembled and administered to a selected patient or patients based on the presence of biomarkers indicating responsiveness to a predesigned set of active ingredients (for example, a peptide warehouse).

Uniquely designed drug product

(UDDP). A drug product specifically defined and manufactured for a specific patient according to individual clinical features that is not intended to be administered to any other individual.

Tumour-specific antigens

(TSAs). HLA ligands exclusively presented on tumours that are not presented on any other tissues.

Stratification

Allocation of a therapy with a defined or invariant drug product based on the presence of one or more specific biomarkers.

Individualization

The fully individualized design of a drug product for a specific patient based on biomarker analyses of an individual tumour or tumours (a variant drug product).

Tumour-associated antigens

(TAAs). HLA-presented peptides present on a tumour that can also be presented on other non-malignant tissues.

Mutated tumour-specific antigens

HLA-binding peptides with tumour-specific alternative sequences (compared with the germline sequence) derived from one of several types of germline mutations including single-nucleotide variants, indels, fusions and others. Synonymously referred to as mutated neoantigens.

Neoantigen

A term commonly used to describe tumour-specific antigens (TSAs). This term has mostly been used to describe mutated TSAs and can cause confusion when also used to describe wild-type sequence TSAs.

Next-generation sequencing

(NGS). Massively parallel sequencing technology enabling the rapid, high-throughput analysis of nucleic acid sequences including those from the whole genome, exome or transcriptome.

Tandem mass spectrometry

(MS/MS). Liquid chromatography followed by two-stage mass spectrometry including ionization of samples followed by detection of the parental mass and the subsequent fragmentation and assessment of respective fragment masses.

Predicted HLA ligands

Amino acid sequences with defined HLA-binding motifs that can be inferred in silico using computational algorithms.

Alternatively spliced TSAs

An HLA-binding peptide with a tumour-specific alternative amino acid sequence (such as that containing a neojunction) derived from alternative mRNA splicing events.

Cryptic antigens

HLA-eluted peptides detected by mass spectrometry that lack clear correlates in the consensus coding sequence (exome).

Proteasomal splicing

Proteasome-catalysed peptide sequence modification through ligation of other liberated protein fragments.

Defective ribosomal products

(DRIPs). Prematurely terminated and misfolded peptides produced from translation of bona fide mRNA in the appropriate reading frames.

Dark matter of the proteome

The proteomic correlate of genomic dark matter, located outside the coding region and assumed not to be translated.

Consensus genomic sequence

The calculated order of most frequent residues, either nucleotides or amino acids, found at each position in a sequence alignment within the genome.

Naturally presented HLA ligands

Peptides presented by MHC that can be detected using MS/MS following MHC immunoprecipitation or by T cell based detection assays.

HLA ligandome

A naturally occurring, non-immunologically validated HLA-presented peptide repertoire, characterized by MS/MS after HLA immunoprecipitation and peptide elution.

Wild-type tumour-specific antigens

HLA-eluted peptides with wild-type sequences (compared with the relevant germline sequence) that nonetheless have tumour-specific presentation, and to which the immune system has not been previously exposed and not represented on benign tissues.

Tumour-specific antigens with reactivated early ontogenic expression

Tumour-specific HLA ligands (compared with the germline sequence) derived from proteins that are usually physiologically restricted to the early stages of ontogenetic expression, including cancer–testis antigens.

Post-translationally modified tumour-associated antigens

HLA ligands with wild-type (or in rare cases also alternative) sequences derived from tumour-specific post-translational modifications.

Overexpressed tumour-associated antigens

An HLA ligand that is typically overexpressed on tumour cells, albeit with lower levels of expression on non-malignant tissues.

Tumour mutational load

The sum total of somatic mutations located in the exomes of cancer cells. Tumour mutational load should not be viewed as equivalent to tumour mutational burden.

Tumour mutational burden

A biomarker used for predicting therapy response in clinical trials that usually reflects the tumour mutational load of selected genes, as assessed primarily using the Foundation Medicine gene panel, but also potentially other assays (such as the MSKCC-IMPACT panel). This term only applies directly to this reduced proportion of mutated genes and does not indicate the entire tumour mutational load.

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Haen, S.P., Löffler, M.W., Rammensee, HG. et al. Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire. Nat Rev Clin Oncol 17, 595–610 (2020). https://doi.org/10.1038/s41571-020-0387-x

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