Abstract
Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies. In this Review, we describe the molecular mechanisms of antigen processing and presentation in tumours and their clinical consequences. We examine how various aspects of the antigen-presentation machinery (APM) shape tumour immunity. In particular, we discuss genomic variants in HLA alleles and other APM components, highlighting their influence on the immunopeptidomes of both malignant cells and immune cells. Understanding the APM, how it is regulated and how it changes in tumour cells is crucial for determining which patients will respond to immunotherapy and why some patients develop resistance. We focus on recently discovered molecular and genomic alterations that drive the clinical outcomes of patients receiving immune-checkpoint inhibitors. An improved understanding of how these variables mediate tumour–immune interactions is expected to guide the more precise administration of immunotherapies and reveal potentially promising directions for the development of new immunotherapeutic approaches.
Key points
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The clinical success of immune-checkpoint inhibitors has improved cancer care, although long-term durable remission is only achieved in a subset of patients.
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Antigen processing and presentation by tumour cells are essential for long-lasting immune surveillance.
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Alterations in the genes encoding MHC components and other parts of the antigen-presentation machinery are frequently found across several cancer types and are associated with both tumour development and the effectiveness of immunotherapies.
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MHC-based antigen presentation exerts strong evolutionary pressure on the immunopeptidome, which in turn shapes the mutational landscape of the tumour genome.
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Germline human leukocyte antigen diversity and somatic aberrations in the antigen-presentation machinery inform the therapeutic response to immune-checkpoint inhibitors.
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Development of novel therapies based on an accurate understanding of antigen presentation in the setting of tumour–immune dynamics is crucial to the development of improved therapeutic approaches.
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Acknowledgements
The authors are grateful for the support from NIH grants R35CA232097 (T.A.C.), R01CA205426 (T.A.C.), U54CA274513 (T.A.C.) and T32CA094186 (K.Y.), a Young Investigator Award from ASCO Conquer Cancer Foundation (K.Y.), a RSNA Research Resident Grant (K.Y.), and a Cleveland Clinic VeloSano Impact Award (K.Y.).
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T.A.C. is a co-founder of and holds equity in Gritstone Oncology; holds equity in An2H; acknowledges grant funding from An2H, AstraZeneca, Bristol Myers Squibb, Eisai, Illumina and Pfizer; has served as an advisor for An2H, AstraZeneca, Bristol Myers Squibb, Eisai, Illumina and MedImmune; and holds ownership of intellectual property on using tumour mutational burden to predict immunotherapy response, which has been licensed to PGDx. K.Y. and A.H. declare no competing interests.
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Yang, K., Halima, A. & Chan, T.A. Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol 20, 604–623 (2023). https://doi.org/10.1038/s41571-023-00789-4
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DOI: https://doi.org/10.1038/s41571-023-00789-4
