B2M and MHC Class I Loss: Hiding From T Cells

Why B2M Is a Single Point of Failure

Every MHC class I heavy chain must pair with B2M to fold correctly and reach the cell surface. There is only one B2M gene, on chromosome 15, so biallelic inactivation removes surface MHC class I entirely, regardless of which HLA alleles the person carries.

Tumour cells with no surface MHC class I are invisible to CD8 T cells. They can, however, become more susceptible to natural killer cells, which are activated by missing MHC class I, so the escape is not complete.

Other Ways the Pathway Breaks

Antigen presentation can also be lost through mutation or downregulation of the transporter TAP1/TAP2, the peptide-loading chaperones, the immunoproteasome subunits, or the HLA genes themselves. Many of these changes are reversible transcriptional downregulation rather than permanent mutation.

Interferon signalling normally upregulates the whole pathway, so defects in interferon response genes indirectly reduce antigen presentation as well.

Clinical Relevance

B2M loss-of-function mutations have been found in tumours that progressed after initial response to PD-1 blockade, and B2M or HLA defects are enriched in checkpoint-inhibitor-resistant tumours across cancer types. They are also common in mismatch-repair-deficient colorectal cancer, where they may blunt but do not abolish immunotherapy benefit.

Testing for antigen-presentation defects is not yet a routine clinical assay, and their presence is one consideration among several rather than a definitive predictor.

Working Around Lost Antigen Presentation

When MHC class I is gone, therapies that do not depend on it become the logical alternative. Natural-killer-cell-based approaches, bispecific antibodies that redirect T cells without MHC restriction, and CAR T cells all bypass the defect, and antibody-drug conjugates and chemotherapy are unaffected by it.

In practice, a B2M or HLA defect found on sequencing is context rather than a directive: it lowers the expected benefit of a checkpoint inhibitor but does not rule it out, since responses still occur, partly through natural killer cells and CD4 T-cell mechanisms. Antigen-presentation testing remains largely a research tool.

Key Takeaways

• ·B2M is required for all MHC class I display, so its loss makes tumour cells invisible to CD8 T cells.
• ·MHC class I loss can also occur through TAP, HLA, proteasome or interferon-pathway defects.
• ·B2M and HLA defects are a recognised mechanism of resistance to checkpoint inhibitors.