"CD4+ T cells have primarily been perceived as helper cells for the activation of CD8+ effector T cells36, which kill tumour cells by direct cytolysis. In our work, we showed that CD4+ effector T cells are also able to independently eradicate established tumours as efficiently as CD8+ cytolytic T cells. Using intravital microscopy, we found that CD4+ and CD8+ effector T cells differ fundamentally in their mode and their site of action in tumour tissues. Only very few CD4+ effector T cells, representing 1% of tumour-infiltrating immune cells, locate at the tumour invasive margins where they interact with CD11c+MHC-II+ antigen-presenting immune cells and indirectly eliminate tumours. By contrast, much larger numbers of CD8+ cytolytic T cells infiltrate the tumour centre where they directly target and kill MHC-I-expressing tumour cells.

Further innate immune stimulation boosted the TH1-directed differentiation of CD4+ T cells, increased the recruitment of immature monocytes into the tumour microenvironment and supported their IFN-dependent activation and differentiation towards antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and IFN-activated mononuclear phagocytes initiate an indirect inflammatory tumour cell death process that acts from the ‘outside-in’ and can be abrogated by neutralizing IFNγ. This unique mode of action operates in parallel to and independent of the direct cytolytic activities of NK cells37 and enables the eradication of MHC-deficient and IFN-unresponsive tumours that evade direct recognition and destruction by CD8+ cytolytic T cells"