Fig. 5: Dynamics of the immune microenvironment in MMRd tumours.

The tumour microenvironment of DNA mismatch repair-deficient (MMRd) tumours is enriched at baseline with a variety of immune cells including CD8⁺ T cells, CD4⁺ T cells, natural killer (NK) cells, dendritic cells and myeloid cells. Classically, these leukocytes are present in an immune exclusion pattern featuring upregulation of immune-checkpoint proteins such as PD-1 and CTLA4. In these cancers, PD-L1 is primarily expressed on immune cells rather than on the tumour cells themselves. In this context, the antitumour immunity mediated by immune-checkpoint inhibitors (ICIs) is only partially dependent on whether the cancer cells are major histocompatibility complex (MHC) class I proficient or deficient. In MHC-I-proficient MMRd tumours, the response to ICIs seems to be mediated by CD8⁺ T cells, whereas in those that are MHC-I-deficient, this response is mediated by CD4⁺ T cells and γδ T cells. The data from patients treated with PD-1 blockade suggest that response is initially characterized by an increase in effector T cells and the production of interferon-γ (IFNγ). MMRd tumours that respond to ICIs are also characterized by B cell infiltration, and data from serial biopsies suggest that the presence of tertiary lymphoid structures (TLS) is a later development. HLA, human leukocyte antigen; TAMs, tumour-associated macrophages; TCR, T cell receptor; ?, potential immune effectors that remain to be determined.