Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

Targeting T cells for cancer immunotherapy commonly fails to generate lasting tumor control. Harnessing additional orchestrators of the immune response against tumors may enhance and broaden clinical benefit. Here, we demonstrate that therapeutic targeting of the IFN{gamma}-IL-12 pathway relies on the amplification of anti-tumoral DC-T cell crosstalk by NK cells. Utilizing an engineered adenoviral platform for paracrine delivery into the tumor microenvironment, we show that IL-12 enhances functional DC-CD8 T cell interactions to generate profound anti-tumor immunity. This effect depends on the abundance of intratumoral NK cells and specifically their capacity to produce the DC chemoattractant CCL5. Failure to respond to IL-12 and other IFN{gamma}-inducing therapies such as immune checkpoint blockade can be overcome by intra-tumoral therapeutic delivery of CCL5 resulting in the recruitment of cDC1s. Our findings reveal novel mechanistic insights how to enhance T cell-NK cell-DC crosstalks, enforcing a tumoreliminating positive feedback mechanism to promote anti-tumor immunity and overcome resistance.