Cross-Talk Between Tumor Cells Undergoing Epithelial to Mesenchymal Transition and Natural Killer Cells in Tumor Microenvironment in Colorectal Cancer

Abstract

Tumor cells undergoing epithelial to mesenchymal transition (EMT) and immune cells in tumor microenvironment (TME) reciprocally influence each other. Immune cells, by supplying TME with bioactive molecules including cytokines, chemokines, enzymes, metabolites, and by physical interactions with tumor cells via their receptors, represent an important factor that affects EMT. Chronical inflammation in TME favorizes tumor growth and invasiveness and stimulates synthesis of EMT promoting transcription factors. Natural killer (NK) cells, owing to their unique ability to exert cytotoxic function independent of major histocompatibility (MHC)-mediated antigen presentation, play a significant role in the control of metastasis in colorectal cancer (CRC). Although, the cross-talk between immune cells and tumor cells in general favors the induction of EMT and inhibition of antitumor immune responses, there are some changes in the immunogenicity of tumor cells during EMT of CRC cells that increase their susceptibility to NK cell cytotoxic lysis. However, suppressive TME downmodulates the expression of activating NK cell receptors, decreases the expression of activating and increases the expression of inhibitory NK cell ligands on tumor cells, and impairs NK cell metabolism that altogether negatively affects the overall NK cell function. Furthermore, process of EMT is often associated with increased expression of programmed cell death ligand (PD-L) and expression of immune checkpoint molecules PD-1, TIGIT, and TIM3 on functionally exhausted NK cells in TME in CRC. In this review we discuss modalities of cross-talk between tumor cells and NK cells, with regard of EMT-driven changes.

Keywords: NK cell receptors; NK cells; colorectal cancer; epithelial to mesenchymal transition; tumor microenvironment.

FIGURE 1

Mechanisms of activation and inhibition of NK cell antitumor activity against tumor cell undergoing epithelial to mesenchymal transition (EMT). The expression of major activating (blue) and inhibitory (red) receptors by NK cells and their ligands on tumor cells determines antitumor activity (cytotoxicity and IFN-γ production). Tumor cells during EMT downregulate the expression of MHC class I and E-cadherin ligands for inhibitory receptors KIRDL (Killer cell immunoglobulin like receptors long cytoplasmic tail) and KLRG1 (Killer Cell Lectin Like Receptor G1), respectively, and upregulate MICA/B and CADM1 ligands for activating receptors NKG2D and CRTAM, respectively, that increases tumor cell susceptibility to NK cell activity. Increased expression of PCNA and galectin-3 ligands for NKp44 and NKp30 receptors, respectively, upregulation of immune checkpoint receptors (PD-1, TIM3, TIGIT) on NK cells and upregulation of PD-1 ligand (PDL-1) and TIM3 ligands (CECAM1, HMGB1) during EMT, have negative effect on NK cell function. Moreover, the expression of MUC-1 protein in tumor cells inhibits NK cell killing of EMT tumor cells via TNF related apoptosis inducing ligand (TRAIL) via inhibition of Bax dimerization. NK cells upregulate the expression of PD-1, TIM3, and TIGIT immune checkpoint receptors that alongside with matrix metalloproteinase ADAM17- induced CD16 receptor shedding in tumor microevent during EMT reduces NK cell activity. Structural motifs involved in activating signaling are green while inhibitory are red: Tyrosine-based motif (YINM) structural motifs and DNAX-activating protein (DAP10) are associated with NKG2D and induce NK cell activation. Immunoreceptor tyrosine-based inhibitory (ITIM) structural motifs are associated with KIRDL, KLRG1, TIGIT, and NKp44 (when ligated to PCNA) receptors during NK cell inhibition. Inhibitory receptor KIRDL suppresses NK cell activity ITIM by recruiting protein tyrosine phosphatase (SHP-1). TIM-3 receptor inhibitory signaling is mediated through Tyrosine 256 (Ty256) structural motif that interacts with HLA-B-associated transcript 3 (BAT3). Fas-associated death domain (FADD) is transmits TRAIL and TRAIL receptor (TRAILR) signaling pathway that is during EMT inhibited by MUC-1 binding that prevents Bax dimerization and apoptosis of tumor cell.