What do cancer-specific T cells ‘see’?

Abstract

Complex cellular interactions between the immune system and cancer can impact tumour development, growth, and progression. T cells play a key role in these interactions, however, the challenge for T cells is to recognise tumour antigens whilst minimising cross reactivity with antigens associated with healthy tissue. Some tumour cells including those associated with viral infections, have clear, tumour-specific antigens that can be targeted by T cells. High mutational burden can lead to increased numbers of mutational neoantigens that allow very specific immune responses to be generated but also allow escape variants to develop. Other cancer indications and those with low mutational burden are less easily distinguished from normal tissue. Recent studies have suggested that cancer-associated alterations in tumour cell biology including changes in post translational modification (PTM) patterns may also lead to novel antigens that can be directly recognised by T cells. The PTM derived antigens provide tumour specific T cell responses that both escape central tolerance and avoid the necessity for individualised therapies. PTM specific CD4 T cell responses have shown tumour therapy in murine models and highlight the importance of CD4 T cells as well as CD8 T cells in reversing the immunosuppressive tumour microenvironment. Understanding which cancer-specific antigens can be recognised by T cells and the way that immune tolerance and the tumour microenvironment shapes immune responses to cancer is vital for future development of cancer therapies.

Modi-2, a vaccine stimulating CD4 mediated responses to homocitrullinated self-epitopes, as a therapy for solid cancers

“…Homocitrullination is induced by cumulative levels of cyanate which results from the breakdown of urea. This also can be mediated through the action of MPO which is secreted by several immune cells including neutrophils, macrophages and MDSCs within inflammatory environments (9). The levels of MPO have been assessed in solid tumours.…”

“…Therefore targeting several epitopes derived from different antigens simultaneously within a vaccine that induces immune responses through several MHC class II alleles helps to overcome tumour immune escape via antigen and HLA loss (31). In addition, the targeting of longer epitope sequences does not exclude the possibility of also stimulating CD8 T cell responses and we have previously shown that CD8 T cell responses can be induced to homocitrullinated peptides (32). However, CD8 T cell responses were not observed to the peptide restricted through the HLA alleles tested in this study and CD4 T cell responses were sufficient to mediate tumour therapy.…”

“…However, many cancers do not possess a high mutational burden and show limited efficacy to checkpoint blockade therapies. Stress-related PTMs alter proteolytic cleavage and can generate neoantigens or neoepitopes which evade self-tolerance (9). In this scenario these cancers may benefit from de novo induction of PTM specific T cell responses via vaccination.…”

T-cell response to checkpoint blockade immunotherapies: from fundamental mechanisms to treatment signatures

“…Tumours are derived from self, making their recognition challenging for T cells that are self-tolerised during thymic development [ 13 ]; nevertheless, T cells can recognise a variety of cancer associated patterns through their TCR [ 14 ], the most potent of which are neoantigens. Neoantigens are novel amino acid sequences arising from nonsynonymous mutations that can deliver a signal to the TCR when presented on MHC molecules [ 15 ].…”