11/20/2023 0 Comments Aaron prodeus![]() 8 The recruited SHP2 functions to suppress T-cell receptor signaling thereby inducing anergy, exhaustion, or apoptosis of tumor-specific T-cells. ![]() ![]() 7 The engagement of PD-1 on T-cells by its ligands present on either tumor cells, cells of the tumor microenvironment, or antigen presenting cells, signals for the recruitment of SHP-2 to the phosphorylated tyrosine of ITIM and ITSM motifs within the PD-1 cytoplasmic tail. 4, 6 In cancer, PD-L1 is often adaptively expressed by cells derived from many tumor types including melanoma, lung, ovarian, and colon in response to IFNγ. While PD-L2 expression is limited to cells of the hematopoietic lineage, 5 PD-L1 is inducibly expressed on most tissues and is a key player in maintaining peripheral tolerance. One key immune inhibitory pathway involves PD-1 interacting with either PD-L1 or PD-L2 (refs. 2 The combined action of all these mechanisms results in the creation of an immunosuppressive tumor microenvironment that explains in part the lack of clinical effectiveness of present-day cancer vaccines aimed at generating tumor antigen-specific T-cell responses. 1 Importantly, tumors also limit immune responses by activating immune inhibitory checkpoint pathways by the cell surface expression of coinhibitory ligands ( i.e., PD-L1, B7-H4, VISTA) within the tumor microenviroment which bind to paired coinhibitory receptors on infiltrating effector T-cells and limit antitumor immune responses. Due to the inherent advantages of aptamers including their lack of immunogenicity, low cost, long shelf life, and ease of synthesis, PD-1 antagonistic aptamers may represent an attractive alternative over antibody-based anti PD-1 therapeutics.Ĭancer cells evade immune surveillance through multiple mechanisms including increased secretion of immunosuppressive cytokines ( i.e., interleukin (IL)-10 and tumor growth factor (TGF)-β), reduced expression of major histocompatibility antigens on their cell surface, the enhanced differentiation of immune effector cells to a regulatory phenotype, as well as an influx of myeloid-derived suppressor cells and tumor associated macrophages. Importantly, the anti-PD-1 DNA aptamer treatment was not associated with off-target TLR-9-related immune responses. ![]() A PEGylated form of MP7 retains the ability to block the PD-1:PD-L1 interaction, and significantly suppresses the growth of PD-L1+ colon carcinoma cells in vivo with a potency equivalent to an antagonistic anti-PD-1 antibody. One such aptamer, MP7, functionally inhibits the PD-L1-mediated suppression of IL-2 secretion in primary T-cells. Here, we report the development of DNA aptamers as synthetic, nonimmunogenic antibody mimics, which bind specifically to the murine extracellular domain of PD-1 and block the PD-1:PD-L1 interaction. Anti-PD-1 antibodies have now been approved for the treatment of melanoma, and are being clinically tested in a number of other tumor types as both a monotherapy and as part of combination regimens. Blocking the immunoinhibitory PD-1:PD-L1 pathway using monoclonal antibodies has led to dramatic clinical responses by reversing tumor immune evasion and provoking robust and durable antitumor responses. ![]()
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