Page 51 - GPD-3-4

Gene & Protein in Disease Immune checkpoint blocker and NK cell activation

developed and are now used in clinical settings. Several activation motif-containing DAP14, activating Zap70 and
studies have demonstrated the efficacy of PD-1-targeting inducing IFN-γ production. 88-90
ICBs. Nivolumab, which inhibits the interaction between In humans, two main ligands, major histocompatibility
PD-1 and its ligand, has shown a higher survival rate complex class I chain (MIC)-related Proteins A and
in patients with non-squamous advanced NSCLC or B (MICA and MICB), bind to NKG2D. MICA/B is
91
squamous NSCLC compared to docetaxel treatment. transmembrane proteins with three extracellular domains,
73
Pembrolizumab and cemiplimab, two other PD-1 inhibitors, which are structurally similar to the α1-α3 domains of the
have also shown significantly improved overall survival in primary histocompatibility class 1a (MHC1a) protein.
92
patients with advanced cutaneous squamous cell carcinoma Some researchers suggest that cells undergoing stress or
and metastatic lung cancer. 73,74 Similarly, atezolizumab and malignant transformation express higher levels of MICA/B
avelumab, two of the monoclonal anti-PD-L1 antibodies, on their cell surface than MHC1 molecules. 93
have shown promising results in NSCLC and renal cell
carcinoma, with response rates of 58% and disease control Strategies focusing on NKG2D/NKG2D-L-mediated NK
rates of 78%. 75-77 cell activation have been widely studied to enhance NK cell
cytotoxicity against target cells. Soluble common γ chain-
2.2. NK cell activation related cytokines, including IL-2 and IL-18, can positively
+
As previously mentioned, NK cells are critical in regulate NKG2D expression in CD16 NK cells. 94,95 A low
immunosurveillance due to their ability to exert direct dose of IL-2 (100 U/mL) combined with IL-18 (175 ng/mL)
cytotoxicity effects without prior activation. The cytotoxicity has been shown to increase NKG2D surface expression in
96
of NK cells is tightly regulated through activating or cancer patients without inducing IL-related toxicity. In
inhibiting receptors. addition to targeting NKG2D on NK cells, recent studies
indicate that increasing NKG2D-L expression on cancer
NK cells are lymphoid elements of the innate immune cell surfaces enhances NK cell-mediated cytotoxicity. For
system, originating from CD34 hematopoietic stem cells example, temozolomide, an alkylating agent that induces
+
in the bone marrow, and have the ability to infiltrate cancer DNA damage, has been shown to increase NKG2D-L
tissues. 78-80 They play a critical role in mediating cytotoxicity expression, leading to tumor suppression. Similarly,
97
and immune regulation in various infections, particularly cisplatin-based adjuvant chemotherapy has demonstrated
in cancer. Unlike cytotoxic CD8 T cells, NK cells do not enhanced NK cell cytotoxicity through the upregulation
+
require pre-stimulation to induce cytotoxic effects. They of MICA through ataxia-telangiectasia-mutated and
achieve this effect through the production of perforin and Rad3-associated protein kinase pathway in NSCLC. 98
granzymes, which facilitate the destruction of transformed
or infected cells. In addition, NK cells can activate and 3. Combination cancer therapy
81
release various cytokines and chemokines, such as IFN-γ Tumor immunology has become a critical component in
and CCL3/4, to enhance adaptive immunity. 82
developing innovative therapeutic approaches to combat
NK cells activate themself through receptors such as the cancer. The main principle of tumor immunology is to
83
NKG2D receptor on their surface. In humans, NKG2D boost the immune response by either activating positive
contains two β-sheets and two α-helices, along with four signals or inhibiting negative signals in various immune
disulfide bonds. Unlike the DNAM-1 signaling pathway, cells. One relatively new era in this field is the use of
84
which utilizes the signaling element on the intracellular ICBs. By targeting ICBs such as PD-1/PD-L1, ICBs
segment, NKG2D interacts with its adaptor proteins, restore the cytotoxic functions of T cells against cancer
DAP10 and DAP12. Alternative splicing of NKG2D cells. NK cells, another population of immune cells,
85
results in the production of two isoforms: NKG2D-S and have also gained increasing attention for their role in
NKG2D-L. The NKG2D-L isoform forms a homodimer, treating metastatic disease. Advances in understanding
which interacts with the transmembrane domain of NK cell cytotoxicity have led to the discovery of several
DAP10 in the cell membrane, leading to NK cell activation promising treatments. For example, certain studies have
through PI3K recruitment and activation through demonstrated the effectiveness of NK cell engager (NKCE)
tyrosine phosphorylation of the Tyr-X-X-Met motif. in targeting NKG2D in the treatment of multiple myeloma.
86
This PI3K activation frequently triggers the activation of CS1xNKG2D, a linked single-chain scFv NKCE that
downstream pathways involving Akt and ERK, triggering targets the tumor surface antigen CS1, has been shown to
Ca mobilization and NK cell-mediated cytotoxicity. In induce dose-dependent cytotoxicity against CS1-positive
2+
87
addition, research suggests that NKG2D-S can interact multiple myeloma cells in vitro. Similarly, 2A9-MICA,
99
with both DAP10 and immunoreceptor tyrosine-based also known as BCMAxMICA, which links the scFv

Volume 3 Issue 4 (2024) 3 doi: 10.36922/gpd.3804