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Microbes & Immunity iPSC-derived NK cell immunotherapy

expressed in B-cell leukemia and lymphoma (37), B-cell cells. Experimental melanoma metastasis also shows
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maturation antigen, found in multiple myeloma (117), that AhR is indispensable for NK cell-mediated cancer
and HER2, associated with lung cancer. Importantly, surveillance. However, some studies have found different
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these targets for CAR-NK cells align with the same roles of AhR. Activating AhR in NK cells promotes the
spectrum of antigens typically targeted by CAR-T cell secretion of IL-10, a suppressive factor for NK cells,
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therapies. However, it is also important to recognize the which acts on IL-10 receptor-positive NK cells. This
differences between CAR-NK and CAR-T therapies. Given mechanism maintains the homeostasis of NK cells in an
the distinct activation mechanisms of NK and T cells, the autocrine and negative feedback manner. Activation
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effects of CAR in enhancing T cell-mediated tumor cell of AhR reduces the cytotoxicity of NK cells by affecting
killing cannot be expected to elevate NK cell performance metabolism-related signaling pathways. AML can evade
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to the same extent. In fact, some studies have found that NK cell-mediated killing by secreting AhR agonists, which
in certain contexts, CAR-NK cells do not demonstrate a inhibit the development and function of NK cells. 124,125
significantly stronger ability to kill tumor cells compared In some solid tumors, the activation of AhR is believed
to unmodified NK cells. to inhibit the anti-tumor activity of T cells, DCs, and
TAMs. Therefore, although AhR is an easily activatable
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4.2. Transcription factors are good candidates for or inhibitable transcription factor, only a few NK cell-
optimizing the anti-tumor ability of NK cell based immunotherapeutic strategies specifically target
Elevating the expression of key transcription factors is a it. More investigation is needed to realize the therapeutic
common strategy to enhance the efficiency of generating potential of AhR in cancer immunology.
immune cells from iPSCs. For example, overexpression of Eomesodermin (EOMES) and T-box expressed in T
SPI1 and CEBPA enhances the differentiation efficiency of cells (T-BET) are two important transcription factors that
microglia, one of the important immune cells in the neural promote the development, function, and cancer-immune
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system. Precise control of the expression of Runx1 surveillance of NK cells, especially for liver-resident
and Hoxa9 during T-cell development can significantly NK cells. 127,128 A recent study showed that remarkable
improve the efficiency of generating T cells from iPSCs. improvements can be achieved in the anti-tumor activity of
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Numerous transcription factors demonstrate promising NK cells by enhancing the expression of T-BET or EOMES
potential as targets for optimizing NK cell-based cancer through genetic modifications. Notably, overexpression
immunotherapies, yet only a select few have been proven in of EOMES has also been found to enhance the ADCC
pre-clinical studies to enhance the tumoricidal capabilities function of NK cells. However, the NK cells in this study
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of NK cells. are derived from HSCs, and the genetic modifications are
Aryl hydrocarbon receptor (AhR) is a ligand-dependent also achieved in CD34 HSCs. If comparable results can
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transcription factor that is widely expressed in immune be replicated in NK cells derived from iPSCs, it would
and non-immune cells. After binding to exogenous or undoubtedly enhance the potential clinical application of
endogenous ligands, AhR translocates to the nucleus and tumor immunotherapy based on NK cells.
regulates the expression of target genes. Many metabolic
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products in the tumor microenvironment can serve as 4.3. Enhanced chemokine response guides NK cells
ligands for AhR. 117,118 Although resting NK cells do not into solid tumors
express AhR at a considerable level, its expression level is As mentioned earlier, one of the factors contributing to
greatly increased in response to cytokine stimulation. It the limited efficacy of NK cell-mediated killing in solid
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is worth noting that co-culturing with IL-21-expressing tumors is reduced migration. Lymphocyte migration and
K562 cells, a common expansion process for iPSC-derived tissue residency are regulated by the interaction between
NK cells, significantly increases the expression level of chemokines and their receptors. Chemokine receptor
AhR. In human peripheral blood NK cells, CD56 bright C-X-C motif Chemokine Receptor 2 (CXCR2) is expressed
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cells possess higher cytokine secretion capacity, lower on many leukocytes but is often lost during the in vitro
cytotoxicity, and higher expression of AhR, compared to culture of NK cells. NK cells overexpressing CXCR2 are
CD56 NK cells. Activation of the AhR signaling pathway similar to control cells in terms of cytotoxicity and IFN-γ
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increases the cytokine-secreting capacity of CD56 bright NK secretion. Furthermore, this overexpression enhances
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cells. Animal experiments have confirmed that AhR is adhesion properties, calcium mobilization specifically
not only a cell-intrinsic requirement for maintaining the in response to CXCR2 ligands, and the ability to migrate
population of liver resident NK cells (possibly ILC1 based down the CXCR2 ligand gradient. CXCR4 is also a vital
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on the markers used in flow cytometry assay) but is also chemokine receptor expressed in both immune cells and
necessary for the memory function of liver resident NK non-hematopoietic cells. The ligand of CXCR4, CXCL12,
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Volume 2 Issue 1 (2025) 34 doi: 10.36922/mi.5653