The remarkable success of immune checkpoint inhibitors demonstrates the potential of tumour-specific CD8+ T cells to prevent and treat cancer. Although the number of lives saved by immunotherapy mounts, only a relatively small fraction of patients are cured. Here, we review two of the factors that limit the application of CD8+ T cell immunotherapies: difficulties in identifying tumour-specific peptides presented by MHC class I molecules and the ability of tumour cells to impair antigen presentation as they evolve under T cell selection. We describe recent advances in understanding how peptides are generated from non-canonical translation of defective ribosomal products, relate this to the dysregulated translation that is a feature of carcinogenesis and propose dysregulated translation as an important new source of tumour-specific peptides. We discuss how the synthesis and function of components of the antigen-processing and presentation pathway, including the recently described immunoribosome, are manipulated by tumours for immunoevasion and point to common druggable targets that may enhance immunotherapy.
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The authors are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and a FLEX project grant from the National Cancer Institute Division of Intramural Research. They thank M. Gumina for careful editing of the manuscript.
The authors declare no competing interests.
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- Law of mass action
The principle that processes are proportional to the concentrations of the participants.
- Phase separation
The creation of distinct compartments from a homogeneous mixture.
- Negative selection
Also known as clonal deletion. The process by which developing lymphocytes expressing potentially autoreactive antigen-specific receptors are induced to undergo apoptosis in the thymus.
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Dersh, D., Hollý, J. & Yewdell, J.W. A few good peptides: MHC class I-based cancer immunosurveillance and immunoevasion. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0390-6