Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance

Abstract

Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands. In this review, we summarize the role of the main non-HLA-specific activating NK receptors, NCRs, NKG2D and DNAM-1, in controlling tumor growth and metastatic spread in solid malignancies affecting the gastrointestinal tract with high incidence in the world population, i.e., pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and gastric cancer (GC), also describing the phenotypic and functional alterations induced on NK cells by their tumor microenvironment.

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

“…This immunosuppressive activity relies on the production of a plethora of cytokines such as IL-4, IL-10, or TGFβ, or metabolites such as ROS or prostaglandin E2; the establishment of a hypoxic microenvironment, or the depletion of trophic cytokines and nutrients, the latter occurring in an indoleamine 2,3-dioxygenase (IDO)-dependent manner, also contribute to dampening NK cell antitumor functions. All these factors may directly interfere with NK cell metabolism, activation, effector functions, or efficient infiltration of the tumor bed; additionally, they may indirectly hamper NK cell activation and functions by inducing the downregulation of activating receptors and/or promoting the upregulation of immune checkpoint ligands [25,26,40,43,46,64,[67][68][69][70][71][72][73][74][75][76][77]. In particular, it was reported that the extent of NKp46, NKp30, and NKG2D downmodulation correlates with tumor progression in human cervical cancer, breast cancer, CRC, and non-small-cell lung carcinoma [67].…”

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

“…Adenosine, via binding to adenosine A2A receptor (A2AR), inhibits metabolic activity (glycolytic capacity and OXPHOS) and effector functions of NK cells (Lokshin et al, 2006;Chambers et al, 2018). Chen et al, 2015;Lorenzo-Herrero et al, 2018;Fedele and Melisi, 2020E-cadherin downregulation Thuault et al, 2006, 2008López-Soto et al, 2013;Chockley et al, 2018 MICA/B, ULBP1 upregulation López-Soto et al, 2006, 2013Bedel et al, 2011;Huergo-Zapico et al, 2014 NK NKG2D, NCR, DNAM1 downregulation Zhang et al, 2012;Rocca et al, 2013Rocca et al, , 2016Schiavoni et al, 2013;Konjevi ć et al, 2019;Ferretti et NK cells compete for amino acids (glutamine, tryptophan, and arginine) with tumor cells and suppressive immune cells (MDSCs, TAMs) and CAFs in TME. Unlike tumors that consume amino acids to provide energy, NK cells utilize amino acids mainly for the maintenance of mTOR and cMyc cellular signaling that are necessary for NK cell functionality.…”

“…During acquisition of mesenchymal-like properties tumor cells often show reduced expression of tumor antigens and immunoproteasome components that altogether lead to reduced presentation of antigenic peptides. Most importantly, tumor cells undergoing EMT decrease the expression of MHC class I molecules, making them resistant to CD8 + T cell cytotoxicity, but more susceptible to NK cell lysis ( Tallerico et al, 2013 ; Ferretti et al, 2020 ; Melaiu et al, 2020 ; Figure 1 ). These changes are associated with the prolonged, i.e., chronic, inflammation in TME, as opposed to the protective, acute inflammation during the early phase of antitumor immune response when type I interferons produced by antigen presenting cells (DCs) and IFN-γ produced by T and NK cells in TME increase the expression of MHC molecules on tumor cells.…”

“…These factors generate a chronic inflammatory immunosuppressive milieu that contributes to the suppression of the antitumor function of NK cells ( Schiavoni et al, 2013 ; Konjević et al, 2017a ). Consequently, decreased expression of NKG2D, NKp30, NKp46, and DNAM1 receptors was reported on NK cells in peripheral blood and tumor tissue of metastatic CRC patients ( Zhang et al, 2012 ; Rocca et al, 2013 , 2016 ; Ferretti et al, 2020 ).…”

HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

“…Engagement of inhibitory NK cell receptors with their cognate ligands will trigger an inhibitory signalling cascade in the NK cells, hence, setting the threshold for activation of the NK cells (12). Activating NK cell receptors, on the other hand, typically interact with ligands that are associated with cellular stress or with viral infection and that are highly expressed on virusinfected or malignant cells (13)(14)(15). An excess amount of activating receptor-ligand interaction will trigger NK cell activation even in the presence of low levels of inhibitory signaling, a condition called "induced-self" (16).…”