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Microbes & Immunity iPSC-derived NK cell immunotherapy

without prior antigen stimulation, in contrast to T cells, of NK cells. The growth of abnormal blood vessels in solid
which require such activation. NK cells are primarily tumors creates hypoxic areas that can cause degranulation
3,4
involved in directly killing target cells and modulating the of NK cells and mitochondrial damage, leading to NK cell
28
activity of other immune cells via cytokine secretion. Their exhaustion. Other tumor-associated cells, such as M2
typical targets include virally infected cells and cells that macrophages or tumor-associated macrophages (TAMs),
have undergone malignant transformation. Originating also weaken NK cytotoxicity. 29,30 Immunosuppressive
5
from hematopoietic stem cells (HSCs) within the bone cytokines in the solid tumor microenvironment, such
marrow, NK cells are not entirely mature upon departure as transforming growth factor-beta (TGF-β) and
from the bone marrow. They undergo further maturation interleukin-10 (IL-10), can reduce the surface expression of
influenced by specific signals and the microenvironment activating receptors, including NKp30, NKG2D, and CD16,
where they reside. 6,7 on NK cells (31 – 33), decrease the levels of transcription
factors such as T-bet (34), and potentially reprogram NK
Peripheral blood NK cells can be categorized into cells into ILC1 cells, which possess a weaker anti-tumor
two primary subpopulations: CD56 bright CD16 and capacity. 31
-
CD56 CD16 . The former represents a mere 5 – 10%
dim
+
of the NK cells circulating in peripheral blood and is For clinical therapies, NK cells are primarily obtained
32
33
thought to be at an early stage in NK cell maturation. In from peripheral blood, cord blood, or established NK cell
34
contrast, the vast majority of NK cells are CD56 CD16 , lines. Although ex vivo-expanded or stimulated NK cells
dim
+
which is indicative of a more mature state. Interestingly, have shown promising safety profiles in clinical applications
the CD56 bright CD16 cells, despite their lower abundance, through autologous or allogeneic transplantation, the full
-
exhibit limited capability for antibody-dependent cell- extent of their therapeutic efficacy awaits further definitive
mediated cytotoxicity (ADCC), a key mechanism through validation. Previous research on NK cells has unveiled
which NK cells mediate their immune response. The numerous genes that exert positive or negative influences
8,9
cytotoxic effect of NK cells is not restricted by the major on NK cell maturation, activation, and their capacity to
histocompatibility complex (MHC), making them combat tumors. Certain genes positively influence NK cells
10
promising candidates for allogeneic transplantation with by fostering their maturation and boosting their cytotoxic
35
favorable clinical prospects. CD16 (Fcγ receptor III), abilities, whereas others act as negative regulators by
36
expressed on the surface of NK cells, facilitates ADCC, impeding NK cell development or dampening their
37
synergizing with adaptive immunity 11,12 and enhancing activation. These insights significantly enrich our
the efficacy of therapeutic antibody-mediated targeted comprehension of NK cell biology and suggest innovative
therapy. During the late stages of NK cell development, avenues for their therapeutic deployment. Targeting these
13
NK cells establish immune tolerance with self-MHC-I regulatory genes presents an exciting opportunity to
molecules through a process known as licensing. The devise novel treatments. Through precise gene editing or
14
15
activating and inhibitory receptors, presented on the molecular modulation, it is possible to improve the anti-
surface of NK cells are in a delicate state of “dynamic tumor potency of NK cells or augment their efficacy within
equilibrium”. 16,17 During the malignant transformation specific immunological niches, enhancing the effectiveness
of normal cells, activating receptor ligands are often of NK cell-based immunotherapies. Strategies that activate
upregulated, whereas inhibitory receptor ligands are or upregulate genes that positively regulate NK cells
frequently downregulated, rendering these cells more could enhance their functional activity and prolong their
susceptible to NK cell-mediated targeting. NK cells longevity. On the other hand, the inhibition or deletion
18
have shown promising clinical prospects in the treatment of genes that negatively regulate NK cells may alleviate
of hematological cancer. 19-22 The graft-versus-leukemia constraints on their functionality, thus bolstering their
(GVL) effect, primarily mediated by NK cells, has garnered anti-tumor performance. Due to significant challenges
in gene transfection and limited expansion lifespan,
increasing clinical attention and is being applied in the both in vitro and in vivo, NK cells encounter constraints
context of human leukocyte antigen (HLA) haplotype- that complicate their genetic engineering and clinical
mismatched HSC transplantation. However, the efficacy utilization. In comparison, T cells, especially chimeric
23
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of NK cell-mediated cytotoxicity against solid tumors is antigen receptor (CAR)-engineered T (CAR-T) cells,
not as ideal as expected. 24,25
demonstrate superior viral transfection rates, enable
The microenvironment of solid tumors is characterized substantial ex vivo expansion, and have the capability to
by low nutrient content, high acidity, and low oxygen, establish enduring memory T cells within the host. These
26
27
39
which negatively affect the function and activation of NK attributes enable CAR-T cells to persistently identify and
cells and other immune cells, resulting in poor cytotoxicity eradicate tumor cells that present specific antigens. On
Volume 2 Issue 1 (2025) 28 doi: 10.36922/mi.5653