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Antigen presentation & immune editing

How the immune system sees cancer, and how cancer learns to hide. Tumours display fragments of their proteins on MHC molecules; T cells kill the ones they recognise; the survivors are the ones that stopped showing fragments or switched on brakes.

Proteasome-processed peptides are loaded on MHC class I (HLA-A/B/C, B2M) and presented to CD8 T cells; dendritic cells cross-present tumour antigens in lymph nodes. Immunoediting proceeds through elimination, equilibrium, and escape: loss of B2M or HLA, JAK1/2 or IFNGR mutations (blunting interferon-γ response), antigen loss, PD-L1 induction, and immunosuppressive niches. Neoantigen quality, not just quantity, predicts response; HLA genotype shapes which mutations are visible. Escape variants explain acquired resistance to checkpoint blockade and CAR-T (CD19 loss).

In one picture

Wanted posters: the cell pins fragments of everything it makes onto its surface. Immune police recognise criminals' faces. Cancers that survive have taken down the posters (lost MHC) or bribed the police (checkpoints).

Diagram

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Proteasome → peptidesTAP transportMHC-I / B2M loadingPeptide–MHC on surfaceCD8 T cell (TCR)IFN-γ → JAK1/2 → STAT1PD-L1 inductionDendritic cell cross-pres…Escape: B2M/HLA loss, JAK…activatesinhibitsdruggable target (click)hit by selected productescape route

How drugs attack it

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  • Checkpoint inhibitors; personalised neoantigen vaccines (intismeran) supply antigen; T-cell engagers and CAR-T bypass MHC entirely
  • TCR-T and ImmTACs (tebentafusp) target intracellular antigens via peptide–HLA
  • Epigenetic drugs and interferon can re-express MHC; MHC-independent NK-cell therapies address MHC-loss escape

Notes

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  • Leading programmes: Schreiber (WashU) coined immunoediting; Chan and Ribas on neoantigen quality and escape (MSK, UCLA); NCI Surgery Branch on neoantigen-reactive T cells; Balachandran (MSK) on long-term vaccine responders.

Key papers

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Connected

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