Tailoring Natural Killer cell immunotherapy to the tumour microenvironment

Abstract

Natural killer (NK) cells are cytotoxic and cytokine-secreting cells that can mediate potent anti-tumour activity. Accumulating evidence indicates that NK cell functions are severely compromised within the confines of the tumour microenvironment thus impairing the efficacy and development of NK cell-based therapies. Here we review the various cellular and molecular pathways that tumours have supplanted to evade NK cell surveillance. We highlight novel strategies designed to alleviate or circumvent the immunosuppressive conditions of the tumour microenvironment in order to emancipate NK cell function and stifle the inexorable growth and metastasis of malignant cells.

Keywords: Checkpoint blockade; Immunosuppression; Immunotherapy; Inhibitory receptors; Natural Killer cell; Tumour microenvironment.

Figure 1. Overview of the endemic cellular and molecular factors that govern NK cell suppression in the tumour microenvironment

Solid tumours contain a complex network of tumour cells (light green), stromal cells, and tumour-infiltrating immune cells (NK cells, light purple), embedded in extracellular matrix (ECM; collagen, dark brown). In response to hypoxic conditions, proliferating tumour cells upregulate HIF-1α that accentuates glycolysis and the generation of immunosuppressive lactate. Tumour cells modify their cell surface glycocalyx to become hypersialylated (light blue cloud) or over-express ECM components e.g. collagen that may engage inhibitory NK cell receptors encoding cytoplasmic Immunoreceptor Tyrosine-based Inhibition Motifs [3] (ITIM, red boxes), such as Siglec-7 and LAIR-1, respectively. Platelets (anucleated, light brown) coat tumour surfaces thus masking ligands (RAET/ULBPs; yellow, blue, magenta and cyan) for activating NK cell receptors like NKG2D or NKp46 that pair with adaptors encoding activating cytoplasmic signalling motifs [3] (green boxes), thus providing a protective shield from NK recognition. Cancer-associated fibroblasts (CAFs; nucleated, light brown) secrete soluble factors that promote angiogenesis (e.g. VEGF; blood vessels, red), tumour growth (e.g. Fibroblast Growth Factors, FGFs), and factors, such as TGF-β, prostaglandin E2 (PGE2) and indoleamine-2,3-dioxygenase (IDO) that can impair the cytotoxic and cytokine secreting functions of NK cells. TGF-β can guide the differentiation of CD73-expressing NK-like ILCs, suggesting tumour-resident CD73-expressing ILCs could potentially contribute to increased concentrations of adenosine in the tumour microenvironment. Finally, a novel population of regulatory NK cells (NK^reg) can secrete IL-22 and suppress the expansion and cytokine secretion properties of tumour-infiltrating lymphocytes via an NKp46-dependent mechanism.