Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment

Abstract

Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.

Keywords: DC-NK cell interaction; NK cells; cellular therapies; dendritic cells; tumor microenvironment.

Figure 1

DC, CD8⁺ T and NK cell interaction within the TME. DCs, CD8⁺ T cells and NK cells may recruit each other into the TME by secreting various kinds of chemokines, like CCL5/XCL1 by NK cells to recruit DCs or CXCL9/10 by DCs to recruit NK and CD8⁺ T cells. Moreover, DCs activates CD8⁺ T cells via tumor antigen presentation and IL-12 production as well as TNFα and IFNγ secretion by NK cells through their own production of IL-12 and IL-18. In return, NK cell derived TNFα and IFNγ induce DC maturation. In addition, NK cells are the major source of the DC growth factor Flt3L. However, tumor cells are able to secret different compounds into the TME, like TGF-ß, soluble MIC A+B or PGE₂, which are all able to down-regulate activating NK cell receptors (e.g. NKG2D and NKp30) resulting in reduced NK cell function and DC-NK cell interaction within the TME.

Figure 2

Treatment strategies to restore anti-tumor surveillance within the TME. Tumor cells can express ligands for various immune checkpoint (ICP) receptors including HLA-E (ligand for NKG2A) and PD-L1 (ligand for PD1), of which the latter one may also be expressed by tumor-infiltrating DCs. Using blocking antibodies against ICP receptors or their ligands restores NK cell function and DC-NK cell interaction. NK cells may further be stimulated by ex vivo generated DC-derived exosomes (Dex). In addition, adoptive transfer of ex vivo generated and engineered DCs (e.g. by transfecting them with a constitutively active IKKß (caIKKß) of the NF-kB pathway to enhance IL-12 production) could improve DC-NK cell interaction and eventually lift immunosuppression within the TME.