Other Name(s): PD-1
Drug Target Analysis Report Drug Target Analysis Report Content

About the Target

Based on the given context information, PD-1 (programmed cell death protein 1) plays a crucial role in immune regulation by interacting with its ligands, PD-L1 (programmed cell death ligand 1) and CD80. PD-L1/CD80 cis-heterodimer formation restricts PD-1/PD-L1 interaction and retains the ability to bind to the CD28 co-stimulatory receptor. However, upregulation of PD-L1 on antigen-presenting cells (APCs) allows the PD-L1/PD-1 trans-interaction, leading to negative regulation of the CD28 signaling pathway and repression of T-cell receptor-induced effector genes [1].

In the context of multiple myeloma (MM), anergic PD-1+ Vgamma9Vdelta2 T cells in the tumor microenvironment (TME) can be rescued from their dysfunctional state by targeting PD-1 and alternative inhibitory checkpoint molecules such as TIM3 and LAG3. This super-anergic state can be overcome by combinations of multiple antibodies targeting these inhibitory checkpoint molecules [2].

In the treatment of non-melanoma skin cancer (NMSC), targeting the PD-1/PD-L1 axis is an effective strategy to activate cytotoxic T-cell responses against tumor cells. Antibodies against PD-L1 (avelumab) and PD-1 (nivolumab, pembrolizumab, cemiplimab) release the inhibitory effects of PD-1/PD-L1 interaction and activate T-cell cytotoxicity [3].

In the broader context of cancer immunotherapy, the blockade of immune checkpoint molecules, including PD-1, has shown promising results in enhancing antitumor immunity. This includes the inhibition of CTLA-4 and PD-1/PD-L1 interactions, which downregulate T-cell responses and protect tumor cells from immune attack [4].

Additionally, PD-1/PD-L1 interaction inhibits the activation of T-cell functions, including Th1 cytokine secretion, T-cell proliferation, and cytotoxicity. The expression of PD-L1 on cancer cells allows it to bind to PD-1 on CD4+ Th1, CD4+ Th2, and CD8+ cytotoxic T cells, resulting in their inhibition [5].

In summary, the PD-1/PD-L1 axis plays a pivotal role in immune regulation and the dysfunction of this pathway can contribute to tumor immune evasion. Targeting PD-1 and its ligands with specific antibodies has shown promising results in overcoming T-cell dysfunction and enhancing antitumor immune responses across various cancer types.
PD-1, or programmed cell death protein 1, is involved in several biological processes and pathways. It plays a key role in the regulation of immune responses and is particularly relevant in the context of HIV infection, cancer, and viral infections such as influenza. In these scenarios, PD-1 can inhibit T cell signaling and suppress immune function. However, blocking the PD-1/PD-L1 axis with monoclonal antibodies has been shown to enhance T cell activation and proliferation, leading to increased antitumor immunity [10].

In the case of HIV, latency reversing agents (LRA), including immune checkpoint inhibitors such as anti-PD-1 antibodies, can induce transcription of viral products, making infected cells "visible" to the immune system and susceptible to virus-mediated cytotoxicity [7].

In influenza and tumor interactions, the PD-1 DIFFL motif, which involves PD-1 and its response circuits, plays a complex role depending on the specific context. In anti-influenza CD8+ T cells, the presence of PD-1 dampens immune responses. Similarly, in the tumor microenvironment, PD-1 can hinder antitumor T cell responses [8]. However, the effects of PD-1 in the context of anti-tumor CD8+ T cells in the influenza-infected lung can be alleviated by PD-1 blockade, allowing for increased expression of NF-kappaB and restoration of T cell signaling pathways [8]. This suggests that PD-1 blockade may have therapeutic potential in enhancing immune responses in these contexts.

In general, the mechanism of PD-1/PD-L1 blockade involves the interaction between PD-1 and PD-L1 inhibiting T cell receptor (TCR) signaling via SHP2. Blocking this axis with antibodies such as atezolizumab, durvalumab, avelumab, nivolumab, or pembrolizumab enhances T cell activation and proliferation [9]. PD-L1 expression can be induced by IFN-gamma release upon TCR activation, and both PD-1 and PD-L1 can be overexpressed in certain conditions, such as in SCCHN (squamous cell carcinoma of the head and neck) [9].

Overall, PD-1 plays a crucial role in immune regulation, and targeting the PD-1/PD-L1 axis with monoclonal antibodies has shown promise in modulating immune responses and enhancing antitumor immunity in various disease contexts [10].

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Note: If you are interested in the full version of this target analysis report, or if you'd like to learn how our AI-powered BDE-Chem can design therapeutic molecules to interact with the PDCD1 target at a cost 90% lower than traditional approaches, please feel free to contact us at BD@silexon.ai.

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