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Microbes & Immunity iPSC-derived NK cell immunotherapy

A crucial step in the NK cell-mediated eradication Inhibitory receptors constitute a pivotal mechanism
of cancer cells is their infiltration into solid tumors. through which NK cells establish immune tolerance. MHC
CXCL14, an important chemokine that promotes NK cell class I molecules serve as the principal ligands for these
migration toward inflammatory or malignant sites, is receptors. Melanoma cells have evolved various strategies
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significantly underexpressed in head and neck squamous to evade immune system surveillance, with one of the most
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cell carcinoma. The presence of hypoxia within the common being the downregulation of MHC-I expression
tumor microenvironment can induce the expression on their surface, allowing them to evade recognition and
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of podoplanin, which disrupts the interaction between elimination by T cells. However, this downregulation also
CCL21 and CCR7, ultimately resulting in diminished renders melanoma cells susceptible to recognition by NK
NK cell migration toward solid tumors and a consequent cells, as they lack the inhibitory signals typically provided
reduction in NK cell cytotoxicity. 61 by MHC-I. While classical MHC-I molecules such as
HLA-B are down-regulated, other non-classical MHC-I
2.3. Altered expression levels of activating and molecules, such as HLA-E or HLA-G, exhibit increased
inhibitory receptors expression in melanoma. 79,80 HLA-E is a crucial ligand
NKp30 (CD337) collaborates with NKp46 and plays a for the CD94/NKG2A inhibitory receptor. Consequently,
pivotal role in the activation of NK cells. The reduction the increased expression of HLA-E renders the cancer
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of NKp30 expression in NK cells from individuals with cells less susceptible to NK cell recognition and attack.
acute myeloid leukemia (AML) profoundly affects NK In contrast to classical MHC-I molecules, non-classical
cell function. This reduction in efficacy extends into MHC-I molecules usually do not present tumor antigens
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the realm of solid tumors, including cervical and breast to T cells. Therefore, increased expression of HLA-E
does not make cancer cells more susceptible to T cell-
cancers, where the malignant cells bind to NKp30, mediated elimination. The concurrent downregulation
inhibiting NK cytotoxicity through the release of galactose
lectin (Gal-3). 64,65 Moreover, colorectal cancer patients of classical MHC-I molecules and upregulation of non-
classical MHC-I molecules equip melanoma cells with
exhibit lower levels of NKp30, NKp44, NKp46, and resistance against T cell-mediated elimination and enable
NKG2D in their peripheral blood NK cells compared to them to escape NK cell-mediated killing simultaneously
healthy individuals. During malignant transformation, (Figure 1). Melanoma-induced exhaustion of NK cells
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the human BCL2-related protein BAG-6 inhibits NKp30- is another mechanism that impairs their function. This
mediated signal transduction, thereby contributing to exhaustion is characterized by impaired cytotoxicity,
immune evasion by tumor cells. 67 cytokine secretion, and response, decreased expression
NKG2D, expressed on NK cells, serves as a critical of activating receptors, and increased expression of
activating receptor. 68,69 However, both virus infections inhibitory receptors. 81
and tumor cells deploy diverse mechanisms to escape 2.4. Induction of NK cell exhaustion
NKG2D-mediated cytotoxicity. 70,71 In cases of HCC, the
expression of NKG2D ligands is diminished through In the tumor microenvironment, cancer cells and other
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the action of the β-catenin signaling pathway. The surrounding cells can induce a state in NK cells similar
expression of the NK cell activating receptor NKG2D is to T cell exhaustion. Macrophages and monocytes in
notably reduced 73,74 in liver cancer. As a consequence, HCC tissues express high levels of CD48, which leads to
NK cells are less easily activated by tumor cells, leading early activation of NK cells through binding to 2B4 and
to diminished cytotoxic effects and a reduced capacity to subsequent dysfunction. When cocultured with monocytes,
release cytokines. Similarly, in non-small cell lung cancer, NK cells derived from the peripheral blood of HCC patients
the enzyme indoleamine 2,3-dioxygenase 1 induces NK show increased expression of Ki67, granzyme B (GzmB),
cell dysfunction by downregulating NKG2D. NK cells CD69, and TRAIL within a short period; however, these
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exposed to activating signals mediated by NKG2D and NK cells ultimately undergo substantial apoptosis. 82
NKp46 downregulate the expression of activating receptors Killer cell lectin-like receptor G1 (KLRG1) was initially
and upregulate checkpoint molecules. This results in considered one of the markers for the maturation of NK
reduced cytokine production and cytotoxicity. Hypoxia cells (117). Subsequent research, however, revealed that
also induces diminished expression of ligands that activate KLRG1 has an inhibitory effect on the activation of NK
NK cell receptors. This includes the downregulation of cells. Similar to T cells, NK cells also express certain
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MICA/B, the ligand for NKG2D, on breast cancer and immune checkpoints. The ligands of KLRG1 primarily
pancreatic cancer cells. This downregulation enables these include molecules related to cell–cell adhesion, such as
cancer cells to evade NK cell-mediated killing. 76,77 cadherin. The expression of cadherin in tumor cells often
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Volume 2 Issue 1 (2025) 30 doi: 10.36922/mi.5653