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

Abstract Current clinically applied cancer immunotherapies largely focus on the ability of CD8+ cytolytic T-cells to directly recognise and kill tumour cells1–3. These strategies are limited by the emergence of MHC-I-deficient or IFN-unresponsive tumour cells and the development of an immunosuppressive tumour microenvironment4–6. CD4+ effector T-cells can contribute to tumour immune defence independent of CD8+ T-cells. However, the potential and the mechanisms of CD4+ T-cell-mediated anti-tumour immunity are incompletely understood7–12. Here, we show how an indirect CD4+ T-cell-mediated mode of action, that is fundamentally different from CD8+ T-cells, enables the eradication of tumours that would otherwise escape direct T-cell targeting. CD4+ effector T-cells preferentially cluster at tumour invasive margins where they engage in antigen-specific interactions with MHC-II+CD11c+ cells, while CD8+ T-cells briskly infiltrate tumour tissues. CD4+ T-cells and innate immune stimulation reprogram the tumour-associated inflammatory monocyte network towards IFN-activated antigen-presenting and tumouricidal effector phenotypes. This results in an amplification loop driving the release of T-cell-derived IFNγ and myeloid cell-derived nitric oxide which cooperatively induce apoptotic death of MHC-deficient and IFN-unresponsive tumour cells that escape cytolytic CD8+ T-cell therapy. Exploiting the ability of CD4+ T-cells to orchestrate indirect inflammatory killing of tumour cells complements the direct cytolytic activity of T-cells to advance cancer immunotherapies.