The Natural Killer-Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

Abstract

Natural killer (NK) cells and dendritic cells (DCs) are crucial mediators of productive immune responses to infection and disease. NK cells and a subtype of DCs, the type 1 conventional DCs (cDC1s), are individually important for regulating immune responses to cancer in mice and humans. Recent work has found that NK cells and cDC1s engage in intercellular cross-talk integral to initiating and coordinating adaptive immunity to cancer. This NK cell-cDC1 axis has been linked to increased overall survival and responses to anti-PD-1 immunotherapy in metastatic melanoma patients. Here, we review recent findings on the role of NK cells and cDC1s in protective immune responses to cancer and immunotherapy, as well as current therapies targeting this NK cell-cDC1 axis. Further, we explore the concept that intercellular cross-talk between NK cells and cDC1s may be key for many of the positive prognostic associations seen with NK cells and DCs individually. It is clear that increasing our understanding of the NK cell-cDC1 innate immune cell axis will be critical for the generation of novel therapies that can modulate anti-cancer immunity and increase patient responses to common immunotherapies.

Keywords: cancer immunology; dendritic cell; immunotherapy; innate immunity; natural killer cell.

Figure 1

The NK cell-cDC1 axis modulates the TME to boost immune responses to cancer. NK cell production of the chemokines CCL5, XCL1, and XCL2 recruits cDC1s to the tumor. Additionally, FLT3L produced by NK cells increases survival and/or differentiation of cCD1s in the tumor. IFN-γ produced by NK cells enhances cDC1 antigen presentation and maturation and leads to cDC1 production of IL-12, which can increase NK cell activity. cDC1s can further modulate NK cell activity through the expression of CD155 and/or CD112 which can signal through inhibitory receptors (TIGIT and CD96) or activating receptors (CD226/DNAM1) expressed on NK cells. Activated cDC1s in the TME upregulate CCR7 and migrate to the tumor-draining lymph node, where they activate naive CD8⁺ T cells. Effector CD8⁺ T cells are recruited to the TME, at least in part, by cDC1-produced CXCL9/10 and, critically, undergo local restimulation by cDC1s. Repriming of CD8⁺ T cells in the TME increases tumor control, patient survival, and improves responses to anti-PD-1 immunotherapy.