CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours

Most clinically applied cancer immunotherapies rely on the ability of CD8(+) cytolytic T cells to directly recognize and kill tumour cells(1-3). These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment(4-6). The ability of CD4(+) effector cells to contribute to antitumour immunity independently of CD8(+) T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified(7-10). Here, we describe a mechanism whereby a small number of CD4(+) T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8(+) T cell targeting. The CD4(+) effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II(+)CD11c(+) antigen-presenting cells. We show that T helper type 1 cell-directed CD4(+) T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4(+) T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4(+) T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8(+) T cells and natural killer cells and advance cancer immunotherapies.

Automated summary

Most clinically applied cancer immunotherapies rely on direct recognition and killing of tumor cells by CD8(+) cytolytic T cells. However, the effectiveness of these strategies is limited by the emergence of MHC-deficient tumor cells and immunosuppressive tumor microenvironment. In this study, researchers have discovered that a small number of CD4(+) T cells can eliminate MHC-deficient tumors that escape CD8(+) T cell targeting. CD4(+) effector T cells cluster at tumor invasive margins and interact with MHC-II(+)CD11c(+) antigen-presenting cells, leading to the activation of tumoricidal myeloid cells. Together, CD4(+) T cells and tumoricidal myeloid cells induce inflammatory cell death and eradicate interferon-unresponsive and MHC-deficient tumors, suggesting a potential strategy to complement current cancer immunotherapies.