NK cells are never alone: crosstalk and communication in tumour microenvironments

Abstract

Immune escape is a hallmark of cancer. The dynamic and heterogeneous tumour microenvironment (TME) causes insufficient infiltration and poor efficacy of natural killer (NK) cell-based immunotherapy, which becomes a key factor triggering tumour progression. Understanding the crosstalk between NK cells and the TME provides new insights for optimising NK cell-based immunotherapy. Here, we present new advances in direct or indirect crosstalk between NK cells and 9 specialised TMEs, including immune, metabolic, innervated niche, mechanical, and microbial microenvironments, summarise TME-mediated mechanisms of NK cell function inhibition, and highlight potential targeted therapies for NK-TME crosstalk. Importantly, we discuss novel strategies to overcome the inhibitory TME and provide an attractive outlook for the future.

Keywords: Cancer; Communication; Crosstalk; NK cells; TME.

Fig. 1

Specialised microenvironments. To characterise the NK cells crosstalk with the TME in more detail, the TME was subdivided into 9 specialised microenvironments. Different specialised microenvironment functions may overlap. The stromal microenvironment represents key stromal cells (tumor-associated fibroblasts and mesenchymal stem cells). Adapted from “Forensic Analysis”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 2

Intercellular communication between NK cells and cancer cells. Gap junctions allow NK cells to communicate directly with cancer cells, allow the influx of Ca2⁺ into cancer cells, and promote granzyme B activity and cancer cells apoptosis. Membrane nanotubes allow NK cells to communicate remotely with cancer cells, where proteins and cytokines accumulate to mediate the lysis of distant cancer cells. Exosomes mediate two-way communication between cancer cells and NK cells and are important mediators of intercellular communication. DAP10, DNAX-associated protein 10. NKG2D, Natural killer group 2 member D. MICA/B, MHC class I chain-related protein A/B. Hsp70, Heat-shock protein 70. NKp44/30/46: Natural cytotoxicity receptor 44/30/46. Created with BioRender.com

Fig. 3

Crosstalk between NK cells and the TME. In the TME, complex crosstalk exists between NK cells and key cellular components in TME, and this interaction affects their respective cellular functions (left panel). In the intricate TME, exposure to enhancement signals promotes NK cell antitumor responses, and conversely, exposure to inhibitory signals puts NK cells in an immunosuppressive state. NK cells are in a dynamic microenvironment, and the functional transition that occurs when NK cells crosstalk with a specialised microenvironment depends on the balance of enhancement signals and inhibitory signals. Specialised microenvironments involve the immune microenvironment, the matrix microenvironment, the cancer stem cell niche, the hypoxic microenvironment, the metabolic microenvironment, the acidic microenvironment, and the microbial microenvironment (right panel). TNFα, Tumor necrosis factor α. IFN-γ, Interferon-γ. IL-15/2/12/18/10, Interleukin-15/2/12/18/10. PGE2, Prostaglandin E2. IDO, Indoleamine 2,3-dioxygenase. TGF-β, Transforming growth factor-β. NKG2A/C/D, Natural killer group 2 member A/C/D. ROS, Reactive oxygen species. TIGIT: T-cell immunoglobulins and ITIM domain. CTLA-4, Cytotoxic T-lymphocyte antigen 4. PD-1, Programmed death-1. A2AR, A2A adenosine receptor. KIRs, Killer immunoglobulin-like receptors. NKp80: Natural cytotoxicity receptor 80. IL-15R, Interleukin 15 receptor. DNAM-1, DNAX accessory molecule 1. LFA-1, Lymphocyte function-associated antigen-1. ICAM-1, Intercellular adhesion molecule-1. MICA/B, MHC class I chain-related protein A/B. PD-L1, Programmed cell death ligand 1. HLA-C/E, Human leukocyte antigen C/E. CXCL9/10, Chemokine (C-X-C motif) ligand 9/10. Adapted from “The Key Role of Neuroinflammation in Neurodegenerative Diseases”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 4

Mechanisms of innervated niche crosstalk with NK cells. Positive stressors enhance the antitumor effects of NK cells via the hypothalamic–pituitary–adrenal axis or the sympathetic nervous system. Likewise, NK cells have positive effects on the nervous system. IFN-γ, Interferon-γ. IL-10/17, Interleukin-10/17. BDNF, Brain-derived neurotrophic factor. Adapted from “Hypothalamic-Pituitary-Organ Axis with Cellular Effect (Layout)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 5

Directions and outlooks for overcoming inhibitory microenvironments. ST, Spatial transcriptomics. Adapted from “Components of Tissue Engineering”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates