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1. Computational Approach for the Development of pH-Selective PD-1/PD-L1 Signaling Pathway Inhibition in Fight with Cancer

   https://doi.org/10.3390/cancers16132295  

   McDowell, Roderick C; Booth, Jordhan D; McGowan, Allyson; Kolodziejczyk, Wojciech; Hill, Glake A; Banerjee, Santanu; Feng, Manliang; Kapusta, Karina (July 2024, Cancers)

   Mok, Samuel C (Ed.)

   Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment. 

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2. Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma

   https://doi.org/10.1007/s00285-023-02027-y  

   Anderson, Hannah G.; Takacs, Gregory P.; Harris, Duane C.; Kuang, Yang; Harrison, Jeffrey K.; Stepien, Tracy L. (December 2023, Journal of Mathematical Biology)

   Abstract Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored. 

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3. Structure and properties of chiral modifiers (R)-(+)-1-(1-naphthyl)-ethylamine and (S)-(-)-1-(2-naphthyl)-ethylamine on Pd(1 1 1) using infrared spectroscopy

   https://doi.org/10.1016/j.apsusc.2022.154962  

   Bavisotto, Robert; Pradipta Roy, Sree; Tysoe, Wilfred T. (January 2023, Applied Surface Science)
4. Nanoparticle Conjugation Stabilizes and Multimerizes β-Hairpin Peptides To Effectively Target PD-1/PD-L1 β-Sheet-Rich Interfaces

   https://doi.org/10.1021/jacs.9b10160  

   Jeong, Woo-jin; Bu, Jiyoon; Han, Yanxiao; Drelich, Adam J.; Nair, Ashita; Král, Petr; Hong, Seungpyo (December 2019, Journal of the American Chemical Society)
5. Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy

   https://doi.org/10.7554/eLife.52253  

   Cui, Xin; Ma, Chao; Vasudevaraja, Varshini; Serrano, Jonathan; Tong, Jie; Peng, Yansong; Delorenzo, Michael; Shen, Guomiao; Frenster, Joshua; Morales, Renee-Tyler Tan; et al (September 2020, eLife)

   null (Ed.)

   Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific ‘GBM-on-a-Chip’ microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients. 

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