Identification of novel CD8+ T cell epitopes in the CT26 tumour model through a peptide filter relation algorithm

Abstract

Cancer represents one of the deadliest diseases in humans, and current approved therapeutic strategies fail to eliminate tumours from patients whilst correlating with the development of numerous side effects. Over the last few years, cancer immunotherapy approaches have proven their utility for the treatment of this disease, showing complete remission in some treated patients. Some components of the immune system, specifically CD8+ T cells, are considered the main effectors of these anti-cancer therapies as these cells can recognize and eliminate cancer cells through a myriad of cytotoxic mechanisms. However, the majority of the most common immunotherapeutic approaches do not take into consideration the epitopes recognised by CD8+ T cells involved in the immune control of tumours. Moreover, different strategies have shown that vaccination with tumour-specific epitopes are able to induce strong and long-lasting CD8+ T cell responses that are associated with tumour regression. Despite this, the identification of these epitopes in the clinical setting is challenging whilst studies regarding the importance of peptide abundance and affinity in the immunogenicity and therapeutic benefit of such peptides are inconclusive.
In order to improve our understanding on the immunodominance patterns of tumour epitopes and their role in the development of anti-tumour responses, we aimed to identify novel CD8+ T cell epitopes and their role in tumour rejection in the widely-tested CT26 colorectal carcinoma model. For this, and using publicly available immune-transcriptomic data, we used a peptide filter relation model that incorporates the cellular abundance of the source protein alongside their predicted MHC-I affinity, in order to rank the candidate peptides in terms of likelihood of being presented at the cell surface of tumour cells. Using this approach, we identified three novel epitopes, which showed a preferential targeting in mice with regressing tumours upon depletion of regulatory T cells, indicating a potential prediction of clinically-relevant epitopes using the peptide filter relation model compared to classical predictions of MHC-I binding affinities. Dextramer assays confirmed the presence of CD8+ T cells specific for these epitopes, which showed similar activation, memory, and exhaustion phenotypes to CD8+ T cells specific for the other two known CT26 epitopes, GSW11 and AH1. Thus, our study highlights the importance of incorporating abundance and affinity parameters for the selection of cancer-derived peptides, which could significantly improve the design of more specific immunotherapy approaches.

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Identifiers

ORCID for Edward James: orcid.org/0000-0001-8638-7928

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