Finding neoepitopes in mouse models of personalized cancer immunotherapy

Abstract

BACKGROUND: Cancer immunotherapy uses one’s own immune system to fight cancerous cells. As immune system is hard-wired to distinguish self and non-self, cancer immunotherapy is predicted to target cancerous cells specifically, therefore is less toxic than chemotherapy and radiation therapy, two major treatments for cancer. Cancer immunologists have spent decades to search for the specific targets in cancerous cells.

METHODS: Due to the recent advances in high throughput sequencing and bioinformatics, evidence has merged that the neoantigens in cancerous cells are probably the cancer-specific targets that lead to the destruction of cancer. We will review the transplantable murine tumor models for cancer immunotherapy and the bioinformatics tools used to navigate mouse genome to identify tumor-rejecting neoantigens.

RESULTS: Several groups have independently identified point mutations that can be recognized by T cells of host immune system. It is consistent with the note that the formation of peptide-MHC I-TCR complex is critical to activate T cells. Both anchor residue and TCR-facing residue mutations have been reported. While TCR-facing residue mutations may directly activate specific T cells, anchor residue mutations improve the binding of peptides to MHC I molecules, which increases the presentation of peptides and the T cell activation indirectly.

CONCLUSIONS: Our work indicates that the affinity of neoepitopes for MHC I is not a predictor for anti-tumor immune responses in mice. Instead differential agretopic index (DAI), the numerical difference of epitope-MHC I affinities between the mutated and un-mutated sequences is a significant predictor. A similar bioinformatics pipeline has been developed to generate personalized vaccines to treat human ovarian cancer in a Phase I clinical trial.

Key words： cancer immunotherapy; tumor antigens; neoantigens; neoepitopes; differential agretopic index (DAI); RNA-Seq; single nucleotide variant (SNV)

Acknowledgements

We acknowledge Dr. Pramod Srivastava for his inspiration, guidance and vision for this article and neoepitope research in general. Having been working on neoepitopes for over 30 years, Dr. Srivastava is a living legend who believes that the only cancer-specific epitopes are those epitopes derived from random passenger mutations from dividing cancerous cells.

Compliance with ethics guidelines

Sahar Al Seesi, Alok Das Mohapatra, Arpita Pawashe, Ion I. Mandoiu, and Fei Duan declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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