Neoantigens originate from tumors and are not present in normal tissues. Research findings indicate that neoantigens have the potential to activate tumor-specific T-cell-mediated antitumor immune responses, making them promising targets for immunotherapy.
Most cancer neoantigens, are unique to the individuals who have them. However, there is a small number of mutations that happen at certain spots within genes that are important for cancer development. These are called hotspot or driver mutations. One example of hotspot mutations occurs in genes from the RAS family. RAS mutations take place in many common cancers. Hence, immunotherapies and therapeutic modality targeting KRAS mutations were developed to control tumor cells in particular T cell immunotherapy targeting KRASG12D/V mutations in the context of specific human leukocyte antigen (HLA) molecules on T cells (1).
Rpl18 neoepitopes are another type of neoantigen originating from the ribosomal protein L18. Rpl18 neoepitopes have elevated levels of expression in MC38 colorectal cancer mouse model. These neoepitopes consist of a unique sequence of amino acids that bind to Major Histocompatibility Complex (MHC) molecules. The use of therapeutic vaccination with synthetic peptides successfully triggered CD8 T cell responses against the mutated Rpl18 epitope, effectively controlling tumor growth in vivo (2). This strong immune response to the mutated Rpl18 epitope plays a crucial role in advancing and refining immunotherapeutic strategies in the MC-38 tumor model (2).
So far, more than 2,000 mutations linked to cancer have been found, but only about 20 (Examples in the table) have been recognized as capable of triggering an immune response and being targeted for treatment (1). There are several factors that can affect how well these cancer-related proteins are recognized by the immune system, such as how much of the protein is made, how it is processed in the body, how well it binds to immune molecules, its stability on cell surfaces, and how effectively T cells, which are a type of immune cell, can identify it.
| Type of mutations | Neoantigens | HLA Restrictions |
| Missense mutations | CDK4 R24C | A*02:01 |
| KRAS G12V | A*03:01, A*11:01, A*30:01, A*68:01, C*01:02, C*03:03, C*03:04 | |
| KRAS G12D | A*03:01, A*11:01, A*68:01, B*07:02, C*03:04, C*08:02 | |
| p53 R175H | A*02:01 | |
| Frameshift indels | NPM1 | A*02:01 |
| TGFβR2 | A*02:01 | |
| Gene translocations | BCR-ABL | A*03:01 |
| Viral oncoproteins | HPV E6 | A*02:01 |
| HPV E7 | A*02:01 | |
| EBV LMP1 | A*02:01 | |
| EBV LMP2 | A*02:01, A*11:01 |
With the advent of new technologies, it’s become more evident that human cancers are very complex, bearing thousands of mutations. These new mutations and expressions of non-synonymous mutation produce neoantigens. The neoantigens are endogenously processed and presented to T cells, subsequent T cells recognize target cells. According to the profile of detected tumor mutations, a personalized cancer vaccine could be designed to target the specific epitopes of neoantigens against cancers. To identify and predict the affinity of neoantigens to MHCs or the immunogenicity of neoantigens requires a combination of algorithms and whole-exome sequencing technology. However, the validation of epitope mapping and MHC/neoantigen binding extends beyond software predictions. The QuickSwitch™ Class Quant Tetramer Kit utilize a patented technique for exchanging up to ten peptides on an MHC Class I and II tetramers. Newly discovered antigens, e.g. from peptide screens, can easily be incorporated in tetramers and used for quantification of CD4+/CD8+ T cell subsets.
References:
1. Martinov, Tijana, and Philip D. Greenberg. "Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor–Based Cellular Therapy." Annual review of cancer biology 7.1 (2023): 331-351.
2. Schrörs, Barbara, et al. "MC38 colorectal tumor cell lines from two different sources display substantial differences in transcriptome, mutanome and neoantigen expression." Frontiers in Immunology 14 (2023): 1102282