Tumour cell vaccines that secrete interleukin-2 (IL-2) and interferonγ (IFNγ) are recognised by T cells while resisting destruction by natural killer (NK) cells

The inoculation into mice of genetically engineered tumour cells that secrete IL-2 or IFNγ results in rejection, while unmodified parental tumour cells grow progressively. In vivo studies demonstrated synergy between IL-2 and IFNγ leading to the rejection of the transduced tumour cells. IL-2 is required for T cell proliferation and differentiation. IFNγ induced the upregulation of MHC class I molecules that present peptides to CD8⁺ T cells. Furthermore, IFNγ can correct defects in antigen processing. Thus, for T cells, IL-2/IFNγ-secreting double cytokine tumour cell vaccines might-serve as class I⁺ peptide/antigen presenting depots for developing effector cells. In contrast to T cells, NK cells exert spontaneous killing and kill class I⁺ targets less well than those that are class I^-. For this reason, they may actually have a detrimental effect by destroying a class I⁺ tumour cell vaccine before adequate T cell stimulation occurs. Based upon this rationale, we tested the hypothesis that an unrecognised benefit of increased class I expression by tumour cells in response to IFNγ secretion would be to enable cytokine-secreting vaccine cells to resist destruction by NK cells. Our results demonstrated that T cells recognised tumour cells secreting IFNγ better than those secreting IL-2. NH cells, in contrast, were inhibited by tumour cells that secreted IFNγ, but not by those that secreted IL-2. The findings suggest that, in addition to upregulating adhesion molecules, MHC molecules, and correcting defects in antigen presentation pathways, IFNγ secretion may protect tumour cell vaccines from early NK-mediated destruction, keeping them available for T cell priming.