Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

Abstract

Natural killer (NK) cells are a population of innate lymphoid cells playing a pivotal role in host immune responses against infection and tumor growth. These cells have a powerful cytotoxic activity orchestrated by an intricate network of inhibitory and activating signals. The importance of NK cells in controlling tumor growth and in mediating a robust anti-metastatic effect has been demonstrated in different experimental mouse cancer models. Consistently, high density of tumor-infiltrating NK cells has been linked with a good prognosis in multiple human solid tumors. However, there are also tumors that appear to be refractory to NK cell-mediated killing for the presence of an immunosuppressive microenvironment affecting NK cell function. Immunotherapeutic strategies aimed at restoring and increasing the cytotoxic activity of NK cells in solid tumors, including the adoptive transfer of NK and CAR-NK cells, are currently employed in preclinical and clinical studies. In this review, we outline recent advances supporting the direct role of NK cells in controlling expansion of solid tumors and their prognostic value in human cancers. We summarize the mechanisms adopted by cancer cells and the tumor microenvironment to affect NK cell function, and finally we evaluate current strategies to augment the antitumor function of NK cells for the treatment of solid tumors.

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

“…Immune suppressive cells, e.g., myeloid derived suppressor cells (MDSC) (20), M2 macrophages (21,22), and regulatory T cells (Tregs) (23), inhibit CTL-and NK cell-effector function in solid tumors (24) via the expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors (25). Indeed, the abundance of MDSC and Tregs in solid tumors positively correlate with advanced disease and increased tumor burden (26)(27)(28), and are independent predictors of poor outcome (29-32).…”

Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production, and secrete monocyte-recruiting and polarizing factors

“…NK cells have been found to be compromised in several cancers [3,6,[9][10][11][12][13]15,18,19,24,25,38]. NK cell contribution to tumour progression goes beyond the mechanism of tumour escape and immunosuppression [3,[10][11][12]24,25] .…”

“…As for several immune cells [3][4][5][6]8], NK cells have been described to acquire a tolerogenic behaviour and to be altered in their cytotoxic activities [3][4][5][6][10][11][12][13][14][15][16], they represent still an under investigated cell population and only few studies demonstrated pro-inflammatory angiogenic cancer cell growth promoting activities in cancers [3,[10][11][12]14]. Major mechanisms associated with impaired NK cell function in cancer patients, are downregulation of lytic perforin/granzyme production accompanied with reduction of degranulation capabilities, together with reduction of NKG2D (the major NK cell activation receptor) expression [17][18][19]. In prostate cancer, the ligands for NKp30 and NKp46 are expressed on NK cells from patients with primary tumours but not on benign prostate hyperplasia [20].…”

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

“…Tumor cells, antigen-presenting cells (APCs), Tregs, and MDSCs in the TME express high levels of PD-L1 and other ligands of immune checkpoint molecules, which prevent NK cell activation, even resulting in NK cell dysfunction or exhaustion (23). Meanwhile, the immunosuppressive TME alters the balance between inhibitory or activating NK cell receptors by downregulating activating receptor expression and upregulating inhibitory receptor expression, including PD-1, TIM-3, LAG-3, NKG2A, and TIGIT, which are referred to as checkpoint receptors.…”

“…Many factors in the TME prevent NK cells infiltrating inside the tumor sites and hamper their activation and anti-tumor activity ( 23 – 25 ). Extracellular matrix components, such as collagen and hyaluronic acid, are densely packed in pancreatic cancer tissues, which prevent NK cells migrating into the tumor bed ( 26 , 27 ).…”