Extended Data Fig. 10: Spatial organisation and dynamics of T-cell effector functions in tumour tissues.

a, Graphical representation of direct antigen recognition and induction of cytolytic cell death. CD8+ and CD4+ effector T-cells can recognise their antigens as peptide epitopes presented by MHC-molecules on tumour cell surfaces and initiate direct killing through the release of cytolytic granules. b, Graphical representation of indirect antigen recognition and remote induction of inflammatory cell death. CD4+ effector T-cells also efficiently recognise tumour antigen on the surface of antigen-presenting cells (APC) including monocyte-derived dendritic cells (Mo-DC) and engage tumouricidal effector cells of the monocyte-macrophage lineage (Mono-Mac effectors) to initiate indirect cell death through the release of pro-inflammatory mediators. c, Spatial organisation and dynamics of direct induction of cytolytic cell death. CD8+ effector T-cells briskly infiltrate tumour tissues, where they directly interact with tumour cells (left), while CD4+ effector T-cells directly interact with tumour cells mainly near the invasive margin (right). d, Spatial organisation and dynamics of remote induction of inflammatory cell death. CD4+ effector T-cells cluster locally at the tumour invasive margin, where they indirectly recognise tumour antigen phagocytosed, processed and presented by dendritic cells. Activated CD4+ T-cells secrete IFNγ leading to the recruitment and activation of monocytes into the tumour tissue. Recruited monocytes phenotypically develop along differentiations path towards IFN-activated antigen-presenting (monocyte-derived dendritic cells, Mo-DCs) and tumouricidal effector phenotypes (monocyte-macrophage effector cells, Mono-Mac effectors). Mo-DCs additionally activate CD4+ T-cells and amplify monocyte recruitment, activation and differentiation. Innate immune stimulation promotes the Th1-directed differentiation of CD4+ T-cells and increases the tumouricidal functions of Mono-Mac effectors. CD4+ T-cell-derived IFNγ sensitises IFN-responsive melanoma cells for TNF-induced cell death. Myeloid cell-derived nitric oxide (NO) contributes to inflammatory cell death of IFN-unresponsive melanoma cells. Taken together, the induction of remote inflammatory cell death by CD4+ T-cells and tumouricidal myeloid cells eradicate IFN-responsive as well as IFN-unresponsive, MHC-deficient tumours that evade direct recognition and cytolytic killing.