The cancer antigenome

Abstract

Cancer cells deviate from normal body cells in two immunologically important ways. First, tumour cells carry tens to hundreds of protein-changing mutations that are either responsible for cellular transformation or that have accumulated as mere passengers. Second, as a consequence of genetic and epigenetic alterations, tumour cells express a series of proteins that are normally not present or present at lower levels. These changes lead to the presentation of an altered repertoire of MHC class I-associated peptides. Importantly, while there is now strong clinical evidence that cytotoxic T-cell activity against such tumour-associated antigens can lead to cancer regression, at present we fail to understand which tumour-associated antigens form the prime targets in effective immunotherapies. Here, we describe how recent developments in cancer genomics will make it feasible to establish the repertoire of tumour-associated epitopes on a patient-specific basis. The elucidation of this 'cancer antigenome' will be valuable to reveal how clinically successful immunotherapies mediate their effect. Furthermore, the description of the cancer antigenome should form the basis of novel forms of personalized cancer immunotherapy.

Figure 1

Distribution of self- versus neo-antigens and their tolerance and toxicity profile. Schematic overview of the different types of antigens that can be potentially targeted by T cells: self-antigens and neo-antigens. Blue denotes the shared antigens between different patients and red represents unique, patient-specific antigens. At present, there is little evidence that shared antigens can be truly patient specific, although some of the shared antigens are only expressed in a fraction of a given human tumour type.

Figure 2

Unravelling the cancer antigenome. First, mutations (red symbols) are determined within the genomic DNA (black lines—either by whole exome or whole genome sequencing) and comparison with normal tissue DNA. Using RNA (blue line) sequencing, the expression of these mutations can be evaluated prior to the prediction phase (optionally) in order to focus on those genes that are expressed within the tumour. Subsequently, epitopes are predicted using algorithms for peptide cleavage and MHC binding, resulting in the description of the antigenome of that tumour. Finally, T-cell assays can be performed, for example, using multiplexed MHC multimer staining, to determine whether T cells recognizing these neo-antigens are present within the patients’ repertoire or whether they can be induced from the naïve T-cell repertoire.

Figure 3

Mutation types within the cancer antigenome. Mutations (red symbols) present in human tumours can be subdivided into three groups. Drivers, mutations that are essential for tumour transformation or growth. ‘Essential passengers’, mutations in genes that cannot easily be deleted by the tumour as it is critical for tumour cell survival and no wild-type copy is present. Mere passengers, mutations that have no impact on tumour growth or survival but can generate T-cell neo-antigens. For the latter mutation type, the likelihood of tumour escape is high compared to driver and essential passenger mutations.