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

Benedikt Jacobs,Veronika Gebel,Victoria Grèze,Evelyn Ullrich,Diana Dudziak,Lukas Heger,Hansjörg Schild

doi:10.3389/fimmu.2021.670540

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.

Highlights

Tumor surveillance is achieved by a complex interplay of the components of the innate and adaptive immune system
natural killer (NK) cells and dendritic cells (DCs) are currently used for immunotherapies to treat tumor patients, for NK cells exhibit the ability to directly eliminate tumor cells without prior sensitization, while DCs are able to initiate an immune response by presenting antigens and inducing tumor-antigen specific CD8+ T cell [2]
IL-15 generated monocyte-derived DCs (moDCs), that were matured with a human papilloma virus (HPV) vaccine, demonstrated a Th1-polarized cytokine profile, and increased the cytotoxicity of NK cells against cervical cancer cell lines [99]

Summary

INTRODUCTION

Tumor surveillance is achieved by a complex interplay of the components of the innate and adaptive immune system. Another group highlighted the role of the NK cell receptor NKG2D and its ligands during NK-DC interaction They demonstrated that upon footpad injection of ectromelia virus, virus-infected murine skin-derived migratory DCs up regulated NKG2D ligands on their surface and migrated to the draining lymph nodes (dLN), where they stimulated IFNg production by NK cells. Data indicated that lower NKG2D levels on NK cells decreased their cytotoxic activity against NKG2D ligand-expressing tumor cells and negatively influence IFN-a-mediated NK-DCinteractions, since NKG2D ligands are up regulated upon IFNa stimulation on DCs. In addition, PGE2 was demonstrated to reduce NKG2D and 2B4 expression on NK cells, which inhibits IFN-g production and cytotoxicity, but potentially effect NK-DC-interactions as well. IL-18-secretion by DCs, which was associated with a reduction of HMGB1-production by NK cells leading to reduced DC maturation [3, 86]

Findings

DISCUSSION

CONCLUSION AND OUTLOOK