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 recognize tumour antigens whilst minimizing 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. A 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 recognized by T cells. The PTM-derived antigens provide tumour-specific T-cell responses that both escape central tolerance and avoid the necessity for individualized 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 recognized by T cells and the way that immune tolerance and the tumour microenvironment shape immune responses to cancer is vital for the future development of cancer therapies.

Keywords: T cells; mutational neo-epitope; post-translational modification; tumour antigen; virus-associated tumour.

Graphical Abstract

Figure 1:

Schematic of post-translational modifications (PTMs) in tumour. Tumour cells are subject to conditions that can lead to altered patterns of PTM. PAD-dependent citrullination of arginine and MPO-dependent homocitrullination of lysine as well as altered patterns of phosphorylation and glycosylation can all occur in tumour cells. Cellular processing can then lead to presentation of these modified epitopes via MHC-I and in the presence of IFNγ, MHC-II. This allows CD4 and CD8 T cells to directly recognize tumour-associated PTMs.