The Natural Killer Cell Interactome in the Tumor Microenvironment: Basic Concepts and Clinical Application

Natural killer (NK) cells are large granular lymphocytes of the innate lymphoid system. As the first responders to sites of inflammation, they possess unique mechanisms for elimination of early malignancy, complementing the adaptive immunity that is subsequently launched against entrenched cancer cells. Despite their high natural cytotoxicity during tumor initiation, NK cells have tremendous, yet unharnessed potential as therapeutic effectors against cancer in situ. This amenability is facilitated by their ability to distinguish healthy self-cells from malignantly-transformed, stressed, or virus-infected cells. Importantly, NK cell-mediated recognition and killing of tumor targets does not require antigen specificity or co-stimulation. Instead, self vs. target cell distinction is governed through negative regulation by inhibitory killer immunoglobulin-like and lectin-like receptor families, as well as checkpoint molecules that when ligated to cognate human leukocyte antigens, enhance or dampen NK cell reactivity. Once recognized, NK cells can then rapidly kill these diseased cells by engagement of death receptors or by exocytosis of cytolytic granules and cytokines that subsequently induce apoptosis. The nature and amplitude of NK cell reactivity are further nuanced by functional and phenotypic diversity among NK cell subsets defined largely by the expression levels of FcγRIIIA and CD56; such as CD56^bright, CD56^dimKIR⁺, NKG2C⁺ adaptive memory, CD69⁺CXCR6⁺ tissue resident and decidual NK cells. NK cell activity is modulated by several mechanisms including malignancy-induced ligands that ligate activating receptors on NK cells and contribute both stimulation and decoy signals. These opposing signals not only enhance tumor recognition and elimination by NK cells via ligation of activating receptors such as NKG2D, but also diminish it via loss of receptor engagement as a result of soluble MHC chain-related antigens (MICA/B), and UL16-binding proteins (ULBPs), as well as other ligands in exosome nanovesicles shed from the tumor cells. Moreover, growth factors, chemokines and cytokines secreted by stromal cells, tumor cells and NK cells further modulate NK cell activation, orchestrate their migration into tumor sites, and regulate their cross-interaction with tumor, stromal cells as well as accessory immune cells in the tumor microenvironment.

In wake of the 2018 Nobel prize in Physiology or Medicine for immune checkpoint regulation for treatment of cancer, we invite submissions of Original Research and Review articles that explore NK cell interactions within the tumor microenvironment and apply this understanding for advancing cancer immunotherapy. In this collection, we also explore the similarities between NK cells and cytotoxic killer T cells, as well as discuss their differences such as receptor ligand interactions in terms of activation-dependent exhaustion, cytokine/chemokine-mediated tropism to the tumor and intercellular cross-talk. Owing to the similarities in regulatory mechanisms between NK and T cell activation, knowledge from T-cell based strategies can thus also be applied to develop novel NK cell-based therapies. In this focused issue we invite articles that show how (i) NK cell subsets traffic to tumor microenvironments, (ii) receptor-ligand and metabolic interactions of NK cells with tumor targets regulate their function and (iii) interactions of NK cells with accessory immune cells such as dendritic cells, T cells or stromal cells such as mesenchymal stem cells and adipocytes impact cancer progression and anti-cancer treatment. We also welcome studies that cover (I) novel molecular strategies for generating off-shelf NK cell cancer immunotherapies; (II) technical advances to generate in vitro and in vivo models to design and analyze NK cell-based immunotherapy approaches as well as (III) microenvironmental interactions of NK cells.

Topic Editor Martin Villalba is a founder of Emercell (http://www.emercell.com/) and Julian Pardo receives research support from BMS. All other Topic Editors declare no competing interests with regards to the Research Topic subject.