Fig. 3. Open questions for research into harnessing the therapeutic potential of tumour-specific CD4⁺ T cells.

a The majority of tumour-reactive CD4⁺ T cells have been found to recognise self-derived antigens, but have thus far only been shown to become activated in the tumour microenvironment (TME) and not in surrounding tissues, suggesting that there may be mechanisms specific to within the TME that permit the breaking of self-tolerance. Another possible avenue for loss of CD4⁺ T cell self-tolerance is the conversion of self-specific Tregs into conventional effector T cells within the TME. b Because CD4⁺ T cells are MHC II-restricted, their activation within the TME requires antigen presentation in the context of MHC II molecules. In principle, MHC II⁺ tumours could directly present antigen and activate CD4⁺ T cells, or antigen presentation could occur indirectly via antigen-presenting cells (APCs) resident within tumours or tumour-draining lymphoid sites. c The mutually reinforcing interaction between myeloid-derived suppressor cells (MDSCs) and regulatory CD4⁺ T cells (Tregs) (above) is a negative mirror image of the APC-effector CD4⁺ T cell synergy that drives the generation of effective immunity (below). Understanding the molecular circuitry is crucial to developing targeted strategies to disrupt and convert these negative interactions into cycles that drive anti-tumour immunity.