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

tumor cells to evade immunosurveillance, the majority Programmed cell death 1, also known as CD279, is
of ICB treatments have focused on enhancing T cell- a receptor that regulates CD8 T cell responses. The
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mediated tumor suppression. In recent years, the United PD-1 receptor contains a single immunoglobulin (Ig)
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States Food and Drug Administration has approved several superfamily domain and a cytoplasmic domain with a
antibodies targeting PD-1 (nivolumab, pembrolizumab, tyrosine-based inhibitory motif and an immunoreceptor
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and cemiplimab) and PD-L1 (atezolizumab and avelumab) tyrosine-based switch motif (ITSM). 45,46 Besides CD8
for clinical use in various cancers, including squamous T cells, PD-1 is expressed at high levels in dendritic
non-small cell lung cancer (NSCLC), metastatic cutaneous cells, activated T cells, and NK cells. 47-49 Its expression is
squamous cell carcinoma, malignant melanoma, renal cell upregulated by transcription factors such as forkhead
carcinoma, bladder cancer, and hepatocellular cancer. 10-18 box protein (FOXO1), interferon (IFN) regulatory factor
Simultaneously, NK cells have gained considerable 9, and NOTCH, 50-52 as well as certain common gamma-
attention due to their direct cytotoxicity against infected chain cytokines such as interleukin (IL)-2, IL-7, and IL-21,
cells or tumor cells without the need for prior activation. 19-21 which recruit the NF-κB-related nuclear factor of activated
Notably, the activating NK cell receptor, NK cell protein T cells c1. 53,54
group 2-D (NKG2D), provides therapeutic opportunities Programmed cell death-ligand 1, also known as
to target different cancer subtypes independently. 6,19,22-30 A B7-H1, is the ligand for PD-1. It is expressed broadly
dual-combination approach involving T-cell ICBs and NK across many immune cell types in the human body but
cell activation could produce synergistic therapeutic effects, is upregulated during inflammatory responses. 55-57 PD-L1
leading to improved treatment outcomes. This perspective is a type I transmembrane glycoprotein belonging to
article aims to discuss the various ICB approaches in T-cell the B7-CD28 family of the Ig superfamily. In addition
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and NK-cell activation and their associated biomarkers for to immune cells, tumor cells can express PD-L1 as a
predicting immunotherapeutic outcomes following ICB means of evading immunosurveillance by inducing
treatment. T cell apoptosis, upregulating IL-10 expression, and
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2. Immune checkpoint blockers (ICBs) and promoting CD8 T cell exhaustion. 58-60 Previous research
NK cell activation has suggested that higher PD-L1 expression in various
cancer types can significantly affect immunosuppressive
2.1. Effects of ICBs on T cells activity by modulating T-cell activation through the T-cell

ICBs are cancer immunotherapies that enhance the receptor-associated protein kinase Zap70-RAS-GTPase-
cytotoxicity of immune cells by targeting immunologic extracellular signal-regulated kinase and CD-28-PI3K-
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receptors on their surface. Compared with other therapeutic Akt serine-threonine kinases pathways.
approaches, ICBs typically provide long-lasting effects with The primary role of the PD-1/PD-L1 pathway is to
lower toxicity to healthy cells. 31,32 inhibit immune cell activity through the interaction of
Under normal conditions, the human immune system PD-1 on the cytotoxicity of immune cells with antigen-
maintains a homeostatic balance between proinflammatory presenting cells (APCs). 62,63 Activation of PD-1 activation
and anti-inflammatory responses through immune through PD-L1 triggers an inhibitory signal through ITSM
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checkpoints. These immune checkpoints are inhibitory or tyrosine phosphorylation, leading to the recruitment of
31
stimulatory receptors expressed by immune cells, allowing SH2-domain-containing tyrosine phosphatase 2 and the
the immune system to regulate its cytotoxicity and prevent downregulation of PI3K, serine/threonine kinase (Akt),
autoimmune reactions. 33-35 In many cancer cases, tumor and ZAP70 or PCK activity, directly inhibiting antigen
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cells within a TME can evade immunosurveillance by either receptor signaling. PD-1 activation also affects cytokines
expressing inhibitory signals that suppress cytotoxic immune production, such as IFN-γ, tumor necrosis factor-alpha
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cells or by shedding stress signals from their surface. Tumor (TNF-α), and IL-2, and can inhibit T-cell proliferation
cells can also promote the accumulation of inhibitory cells, while downregulating the anti-apoptotic protein
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such as regulatory T cells (Tregs) or stromal cells, within BCL-xL. Within the TME, the PD-1/PD-L1 pathway
the TME. 33,35-41 By blocking these immune checkpoint is associated with epithelial-mesenchymal transition,
functions, exhausted T cells can be restored to their normal tumor malignancy, and tumor cell proliferation in various
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function. 32,42 A major focus of ICB treatments is on CD 8 T cancers, including breast, lung, and bladder cancers.
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cells, with antibodies targeting the PD-1/PD-L1 pathway It has been hypothesized that blocking these inhibitory
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or CTLA-4 being widely used in clinical practice. This pathways could prevent immune cell exhaustion, even in
5,7
perspective article will specifically focus on the PD-1/PDL1 the TME. Therefore, various inhibitors of PD-1/PD-L1
pathway as a key target in T-cell ICB therapy. (many of which are monoclonal antibodies) have been
Volume 3 Issue 4 (2024) 2 doi: 10.36922/gpd.3804