Abstract
Tumor progression is typically accompanied by an accumulation of driver and passenger somatic mutations. A handful of those mutations occur in protein coding genes which introduce non-synonymous polymorphisms. Certain substitutions may give rise to novel, tumor-associated antigens or neoantigens, presentable by cancer cells to the host adaptive immune system. As antigen recognition is the core of an effective immune response, the identification of patient tumor specific antigens derived from transformed cells is of importance for immunotherapeutic approaches. Recent technological advances in DNA sequencing of tumor genomes, advances in gene expression analysis, algorithm development for antigen predictions and methods for T-cell receptor (TCR) repertoire sequencing have facilitated the selection of candidate immunogenic neoantigens. In this regard, multiple research groups have reported encouraging results of neoantigen-based cancer vaccines that generate tumor antigen specific immune responses, both in mouse models and clinical trials. Additionally, both the quantity and quality of neoantigens has been shown to have predictive value for clinical outcomes in checkpoint-blockade immunotherapy in certain tumor types. Neoantigen recognition by vaccination or through adoptive T cell therapy may have unprecedented potential to advance cancer immunotherapy in combination with other approaches. In our review we discuss three parameters regarding neoantigens: computational methods for epitope prediction, experimental methods for epitope immunogenicity validation and future directions for improvement of those methods. Within each section, we will describe the advantages and limitations of existing methods as well as highlight pressing fundamental problems to be addressed.
Highlights
Successful targeting of immune checkpoints including cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has achieved durable regressions in a wide range of human cancers
Unlike tumor-associated antigens (TAA) that are shared between tumor cells and normal tissue (e.g., Melan A/MART-1) neoantigens have a selective potential to elicit tumor exclusive T cell responses which makes them key elements for inclusion in cancer vaccines and as the basis for adoptive T cell transfer approaches [10,11,12,13,14]
Our group recently proposed the concept of “neoantigen quality” [26, 27]. This concept combines biophysical, chemical and computationally inferred properties of a neoantigen that make it more likely to induce a productive immune response against the tumor. These properties may include affinity of a neoantigen to major histocompatibility complex (MHC), avidity of the peptide-MHC complex to the recognizing T-cell receptor (TCR), type of T cells responding to the neoantigen and sequence similarity to known highly immunogenic epitopes (Figure 1)
Summary
Successful targeting of immune checkpoints including cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has achieved durable regressions in a wide range of human cancers (referred to as checkpoint blockade). Far, MHC-I affinity is the only parameter which can be predicted with some reliability using neoantigen peptide and patient HLA allele sequences in silico, by using several computational tools. These properties may include affinity of a neoantigen to MHC, avidity of the peptide-MHC complex to the recognizing TCR, type of T cells responding to the neoantigen and sequence similarity to known highly immunogenic epitopes (Figure 1).
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