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

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.

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection.

Atopic individuals show enhanced type 2 immune cell responses and a susceptibility to infections with certain bacteria and viruses. Although patients with allergic diseases harbor normal counts of circulating neutrophils, these cells exert deficient effector functions. However, the underlying mechanism of this dysregulation of neutrophils remains ill defined. Here, we find that development, aging, and elimination of neutrophils are accelerated in mice with a predisposition to type 2 immunity, which, in turn, causes susceptibility to infection with several bacteria. Neutrophil-mediated immunity to bacterial infection was greatly decreased in mice with a genetic or induced bias to type 2 immunity. Abrogation of interleukin-4 (IL-4) receptor signaling in these animals fully restored their antibacterial defense, which largely depended on Ly6G+ neutrophils. IL-4 signals accelerated the maturation of neutrophils in the bone marrow and caused their rapid release to the circulation and periphery. IL-4-stimulated neutrophils aged more rapidly in the periphery, as evidenced by their phenotypic and functional changes, including their decreased phagocytosis of bacterial particles. Moreover, neutrophils from type 2 immune predisposed mice were eliminated at a higher rate by apoptosis and phagocytosis by macrophages and dendritic cells. Collectively, IL-4 signaling-mediated neutrophil aging constitutes an important adaptive deficiency in type 2 inflammation, contributing to recurrent bacterial infections.