NK recruited cells including differentiated malignant cells, cancer

NK cells anti-tumor activity are modulated by tumors microenvironment

Histologically, STs introduce as a “complex ‘rogue’ organs” which characteristics by a heterogenic mixed population of malignant and non- malignant (transformed cells and recruited cells) cells into a tumor-specific ECM (1). Generally, through a paracrine, autocrine, and juxtacrine network, tumor microenvironment (TME) creates by interaction batwing the malignant and non-malignant cells (1, 2). Moreover, tumor heterogenic structure and TME are the main determinative elements for the STs development, responses to treatments, and also NK cells activity (5).  Due to this circumstance, we will review solid malignancies microenvironment and its inhibitory roles in NKs activity and anti-tumoral function.  

3.1.    Solid tumors microenvironment

By the several histopathological study, varies kind of transformed and recruited cells including differentiated malignant cells, cancer stem cells (undifferentiated malignant cells) (CSCs), tumor associated fibroblasts (TAF), mesenchymal stem cells (MSCs), adipocytes, pericytes, vascular endothelial cells (VECs), lymphatic endothelial cells (LECs), and infiltrated immune cells such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAMs), T regulatory (T-reg) cells as well as T lymphocytes, B lymphocytes, and also NK cells have defined  as the main cellular population of the STs (1-4). These cells through secretion kinds of paracrine and autocrine factors (growth factor, cytokine, and chemokines) and via inducing their related signaling pathways can control the anti-tumor activity of the NK cells (6) (Figure 1). 

By the several studies, a relationship between the poor prognoses in cancer patients several and high intra-tumor recruitment of immunosuppressive cell including TAM, T-reg, and also MDSC have shown (7-10). Also, an inhibitory response to the NKs anti-tumor activity resulted from an intra-tumoral accumulation of those immunosuppressive cells have shown (6). It seems that, secretion of some key factors such as transforming growth factor-beta (TGF-?), interleukin-10 (IL-10), arginase-1, nitric oxide (NO), indoleamine-2, 3-dioxygenase (IDO), prostaglandin E2 (PGE2), and reactive-oxygen species (ROS) into the STs microenvironment, NK cells responses against the tumors hinder (6-10). On the other hand, in response to secretion of immunosuppressive factors, expression of the NK cells activator cytokines and chemokines significantly inhibit which it case to inhibition of NKs intra-tumoral infiltration and tumor cell killing (11). Hence, targeting the STs microenvironment and/or administration of ex vivo activated NK cells can be an effective and determinative approach for this challenge.  

3.2    Cellular activity of the NK cells in tumors microenvironment

The NKs anti-tumor activity into the STs microenvironment switched by stimulation of the NK cells oligomeric activating receptors including DAP10 (NKG2D), inhibitory MHC class I–specific receptors (NKs cytotoxicity receptors (NCRs), CD16, KIR-S, NKG2C/E), and ITAM-bearing molecules (KIR-L and NKG2A) (12-15). Those mentioned proses are strangely induced via expression of MHC class I polypeptide-related sequence A (MICA), MHC Class I Polypeptide-Related Sequence B (MICB), and UL16 binding protein 1-3 (ULBP1-3) from the malignant tumor cells (16, 17).

The stimulated NK cells through starting chains of paracrine/ autocrine pathways into the STs microenvironment case to cellular death and inhibition of tumor cells survival. Briefly, MAPK/ERK signaling pathway (also known as the Ras-Raf-MEK-ERK pathway) activates immediately after NCRs stimulation in a tumor aggressive NK cell. Promotion of the MAPK/ERK cascade directly ledes to the expression some of the main cytokine genes such as INF-?, tumor necrotic factor-alpha (TNF-?), and also granulocyte-macrophage colony-stimulating factor (GM-CSF) (18-20). In the way of this cascade, autocrine effects of the INF-? directly stimulates interferons receptor (INFsR) and fallowing them activates JAK-STAT signaling pathway which it case to the expression of TNF-related apoptosis-inducing ligand (TRAIL) (21). Also, paracrine stimulation of INFsR via secreted INF-? in tumor cells leads to expression of first apoptosis signal receptor (FAS) (22). On the other hand, activation of extracellular signal-regulated kinases 1/ 2 (ERK1/ 2), as one of the MAPK/ERK signaling pathway mediators, case to formation and exocytosis of the cytotoxic granolas from the NK cells cytoplasm to the membrane, localization and accumulation of Fas ligand (FASL or CD95L) on the NK cells surface, and finally release of granzymes (kinds of serine proteases) (18-20).  In this cascade, tumor cells apoptosis has induced by stimulation of TRAILR and FAS via NK cells TRAIL and FASL ligands and also activation of caspase-3 related cascade which induced by granzymes secretion (23) (Figure 1).