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Microbes & Immunity iPSC-derived NK cell immunotherapy

the other hand, genetically engineered NK cells encounter inhibition mechanisms is vital for the development of
difficulties in achieving adequate cell quantities with the targeted therapies that enhance the antitumor efficacy of
desired genetic payload, maintaining effectiveness in vivo, NK cells. This includes employing genetic modifications or
and overcoming the immunosuppressive forces of the engineering, notably those based on iPSCs, to bolster their
tumor microenvironment. These challenges significantly tumor-killing capacity.
limit the utilization of NK cells in the arena of cancer
immunotherapy. 2.1. Influences on NK cell maturation in peripheral
tissues
Induced pluripotent stem cells (iPSCs), a type
of pluripotent stem cells derived from terminally In human peripheral blood, NK cells can be categorized
into two distinct groups based on the intensity of CD56
differentiated cells, can be efficiently induced to expression: CD56 bright and CD56 . Cells in the CD56
40
dim
dim
differentiate into NK cells through specific combinations subset express higher levels of CD16, a crucial Fc receptor
of cytokines. iPSC-derived NK cells have demonstrated necessary for ADCC mediated by NK cells. CD56 NK cells
41
dim
promising anti-tumor activity in pre-clinical and clinical are generally considered more mature than their CD56 bright
experiments, making them a highly potential therapeutic counterparts. The population of CD56 CD16 NK cells,
dim
+
strategy for NK cell-based cancer treatment. Compared which have cytotoxic function in the peripheral blood,
42
to peripheral blood NK cells, iPSCs are more flexible to is significantly decreased in hepatocellular carcinoma
gene overexpression, gene silencing, and gene editing. (HCC) patients. This is accompanied by a reduction in the
Coupled with the inherent ability of iPSCs for limitless production of granzyme and interferon (IFN)-γ. Moreover,
proliferation, this technology supports the feasibility of the number of CD56 CD16 cells infiltrating liver tumors
dim
+
selecting and purifying genetically modified cells. These is much lower than that in non-tumor regions. In addition,
24
advancements not only establish a foundation for precise human NK cells can be further stratified into the four-
genetic manipulation of NK cells but also open avenues for subset model based on the expression levels of CD11b and
further NK cell research and their application in clinical CD27. Non-small cell lung cancer tumors are infiltrated
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settings. This review explores iPSC-based approaches, by a large number of CD56 CD11b CD27 double negative
-
+
-
particularly genetic modifications, to enhance NK cell- NK cells. These double-negative NK cells are considered
based strategies for combating solid tumors. It covers relatively immature, exhibit lower susceptibility to
the biological characteristics of tissue-resident NK cells, activation, and their presence is positively correlated with
challenges related to the resistance of various solid tumors tumor malignancy. 47,48
to NK cell-mediated cytotoxicity, and clinical efforts aimed
at improving NK cell-mediated killing of solid tumors. 2.2. Changes in cytokine levels (including
chemokines)
2. Mechanisms employed by solid cancer to TGF-β stands as a pivotal immunosuppressive factor for
evade NK cell attack NK cells, impeding their capacity to eliminate target cells,
NK cells and CD8 T cells exhibit parallel cytotoxic release cytokines, and attenuate the expression of activating
+
capabilities, sharing the ability to eliminate target cells receptors. 49,50 On lung cancer cells, TGF-β downregulates
through similar mechanisms, such as employing perforin the expression of ligands for NK cell activating receptors,
and granzyme B. Despite these shared cytotoxic such as NKG2DLs, thereby facilitating cancer cells’ evasion
43
mechanisms, the activation pathways and tumor cell from NK cell-mediated destruction. 51,52 Extensive evidence
recognition strategies of NK cells and T cells differ has firmly established that a diverse range of substances
fundamentally, often standing in stark contrast to each contribute to the development, migration, and increased
other. This distinct divergence in recognition strategies malignancy of lung cancer by modulating the TGF-β
44
suggests that T cells and NK cells offer complementary signaling pathway. 53-55
approaches to tumor cell identification. In this context, it is IL-10 represents another cytokine that inhibits the
critical to delve into the strategies employed by tumor cells functionality of NK cells. Although NK cells and immature
to evade NK cell-mediated destruction. These strategies dendritic cells (DCs) have the ability to activate each
span a broad spectrum, ranging from evading NK cell other, it has been observed that NK cells can also kill DCs
detection to manipulating the NK cell activation processes. that express CD40 or are derived from the activation of
In addition, the tumor immune microenvironment plays a IL-10. 56,57 In the lung tumor microenvironment, NK cells
pivotal role in suppressing NK cells, even after they have not only exhibit reduced cytotoxicity but also play a role
recognized tumor cells and are primed to execute their in negatively regulating DC maturation, thereby assisting
cytotoxic function. Understanding these evasion and tumors in evading immune surveillance. 58
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Volume 2 Issue 1 (2025) 29 doi: 10.36922/mi.5653