Overview of PD-1/PD-L1 Signaling Pathways in Cancer

The latest research has given researchers improved knowledge of the components that suppress the anticancer immune response, ensuing in the development of various medicines that target immunological costimulatory and inhibitory checkpoint pathways. The PD-1/PD-L1 axis, which plays a crucial role in carcinogenesis, may be regulated by various signals in cancerous cells (Figure 1). Therefore, studying this signaling network to advance the current understanding is crucial. Tumor-inducing advanced checkpoint molecules mediate antitumor immune suppression like PD-1. The PD-1/PD-L1 pathway adversely controls the immune system in standard conditions [7]. When PD-1 adheres to PD-L1, it is phosphorylated and subsequently increases immunological suppression by activating some intracellular pathways, which is an important location for PD-1’s biological actions [8]. It is noteworthy that PD-1 affects T and B cells differently via different specific pathways [9]. The PD-1/PD-L1 pathway arose physiologically due to the requirement to limit the level of inflammation at antigen-expressing sites to protect healthy tissue from harm. There is a high expression level of PD-1 on the exterior of all activated T cells [10]. An inflammatory recognizes that it is triggered when a T cell identifies an antigen presented by the MHC complex on a target cell. This results in the production of pro-inflammatory cytokines. The PD-1/PD-L1 axis, which is very important in carcinogenesis, may be modified in cancer cells by various signals. Consequently, it is essential to maintain vigilance over this signaling network to advance our understanding (Figure 1). On the cell membrane, PD-L1 is strongly expressed by cancer cells [11]. Cancer cells can dodge immune surveillance and killing because of the negative signals produced when PD-L1 binds to PD-1 in T cells. These signals cause T cells to die and decrease immunocompetence. Furthermore, the differentiation of memory T cells (Tm) and effector T cells (Tef), as well as the differentiation of exhausted T cells (Tex) and regulatory T cells (Treg), is negatively impacted by the activation of the PD-1/PD-L1 pathway, both of which significantly inhibit the immune effect of T cells [12]. By causing the release of cytokines and cytotoxins, the interaction of PD-L1 to PD-1 also prevents the growth of tumor-specific T lymphocytes and triggers death [13]. Cancer cells can also use the circulatory system to carry PD-L1 (carried in exosomes) to distant areas. Therefore, before they reach metastatic tumors, they can remotely suppress T-cell activation [14,15,16]. By stimulating PTEN, PD-1 prevents TCR-induced activation of the PI3K/AKT pathway [17]. In addition, PD-1 reduces T-cell proliferation by preventing the RAS-MEK-ERK pathway from being activated [18]. IFN-γ and IL-2 production by T cells is reportedly decreased by PD-1 because it prevents PKC from becoming activated [19]. Moreover, by inhibiting glycolysis and encouraging fatty-acid and oxidation lipolysis, PD-1 signaling controls T-cell metabolism [20].

A monoclonal anti-programmed death-1 antibody called JemperliTM, dostarlimab-gxly (Dostarlimab) is produced by GlaxoSmithKline (GSK) with permission from AnaptysBio Inc., San Diego, CA, USA, for the diagnosis of multiple cancers, which include ovarian cancer, endometrial cancer, head and neck cancer, peritoneal cancer, pancreatic cancer, and malignant melanoma. It has been demonstrated that the immune-checkpoint receptor known as PD-1 can inhibit immune responses directed specifically towards cancer [21]. Dostarlimab is a mouse hybridoma-derived humanized IgG4 monoclonal antibody. In order to function, it binds to a PD-1 receptor and inhibits its function. Additionally, it blocks the ligands (PD-L1 and PD-L2) from interacting with the receptor, which activates T cells and restores immune function. Dostarlimab is approved for use in the treatment of adult patients with mismatch repair deficiency (dMMR) and recurrent or advanced endometrial cancer in the United States of America [22,23] and the European Union [24,25]. Dostarlimab, marketed by GlaxoSmithKline as Jemperli, received expedited approval from the FDA in April 2021 [26]. This rapid approval was only given for the treatment of dMMR endometrial malignancies; hence, it was authorized with companion diagnostic equipment called the VENTANA MMR RxDx Panel, which is used to select patients who are suitable candidates for treatment [26].

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