T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance.

NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity

Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital Basel, 4031 Basel, Switzerland.

Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland.

Immune Cell Biology, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.

Microscopy Core Facility, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.

Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, 1066 Amsterdam, Netherlands.

Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland.

Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany.