MHC Class I Antigen Presentation in Cancer Immunotherapy

MHC class I molecules are central to the detection of intracellular abnormalities by CD8+ T lymphocytes. They bind peptide fragments derived from proteasomal degradation of cellular proteins and display them on the cell surface. In the context of malignancy, efficient antigen presentation is critical for immune recognition and eradication of transformed cells. Tumours employ diverse mechanisms to evade this surveillance, including downregulation of MHC-I heavy chains, loss or mutation of beta-2-microglobulin and altered peptide processing. Such defects diminish neoantigen display, compromise the efficacy of immune checkpoint inhibitors and foster resistance to adoptive T cell therapies. Contemporary strategies seek to restore or enhance antigen presentation through epigenetic modulation, targeted small molecules that upregulate antigen-processing machinery, and the activation of immunoproteasome subunits to improve peptide repertoire. A deeper understanding of MHC-I pathway regulation offers promising avenues for overcoming immune escape and refining personalised immunotherapeutic approaches.

Research from Nature Portfolio

Innovative transcriptomic analyses have revealed widespread dysregulation of class I HLA expression across multiple tumour types. One large-scale study employed allele-specific methods to quantify HLA loss of heterozygosity, mutation and alternative splicing, uncovering prevalent transcriptional repression and splicing events that correlate with metastasis and reduced neoantigen burden in lung and breast cancers. These findings underscore the impact of non-genetic HLA disruption on tumour evolution and immune escape. Complementary investigations into mechanisms of clinical resistance have identified inactivation of key antigen presentation components such as beta-2-microglobulin. Loss or mutation of this molecule was disproportionately observed in patients failing checkpoint blockade, establishing a direct link between β2M defects and therapeutic non-responsiveness. Together, these studies highlight both the genomic and transcriptomic vulnerabilities of the MHC-I pathway and suggest novel biomarkers for predicting and overcoming immunotherapy resistance.

MHC Class I Antigen Presentation in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in mhc class i antigen presentation in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Major histocompatibility complex class I (MHC-I): A set of cell-surface proteins that present endogenously derived peptides to CD8+ T cells.

Beta-2-microglobulin (β2M): An invariant light chain required for stable expression of MHC-I molecules at the cell surface.

Immunoproteasome: An inducible form of the proteasome that generates peptides optimised for MHC-I presentation under inflammatory conditions.

Loss of heterozygosity (LOH): Genetic deletion or inactivation of one allele at a gene locus, often leading to reduced antigen presentation function.

Neoantigen: A novel peptide generated from tumour-specific mutations that can be recognised as foreign by the immune system.

References

1. Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Molecular Cancer (2023).
2. MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution. Nature Genetics (2024).
3. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nature Communications (2017).
4. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Frontiers in Immunology (2021).
5. Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma. Nature Communications (2020).
6. Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response. Frontiers in Immunology (2022).