Notes

Cycloartane-type triterpenoids from your complete vegetation of Macrosolen bidoupensis.
Macromolecule drugs particularly antibody drugs are very powerful therapies developing rapidly in the recent 20 years, providing hopes for many patients diagnosed with "incurable" diseases in the past. They also provide more effective and less side effects for many afflicting diseases, and greatly improve the survival rate and life quality of patients. In the last two decades, the proportion of US Food and Drug Administration (FDA) approved macromolecules and antibody drugs are increasing quickly, especially after the discovery of immune checkpoints. To crown all, the 2017 Nobel prize in physiology or medicine was given to immunotherapy. In this chapter, we would like to summarize the current situation of macromolecule and antibody drugs, and what effort scientists and pharmaceutical industry have made to discover and manufacture better antibody drugs.Originally treated as part of a cellular waste, extracellular vesicles (EVs) are being shown to possess a vast variety of functions, of which exosome is the most studied one. Most cells, such as tumor cells, immunocytes, and fibroblasts can secrete exosomes, especially under certain stresses the amount is much higher, and the contents of exosome represent the status of the donor cells and the tumor microenvironment. As crucial transporters for cells' content exchange, much attention has been raised in the utilities of exosomes to suppress immune response, and to modify a microenvironment favorable for cancer progression. Panobinostat datasheet Exosomal immune checkpoints, such as programmed cell death ligand 1 (PD-L1), contribute to immunosuppression and are associated with anti-PD-1 response. Many forms of soluble immune checkpoint receptors have also been shown to influence efficacy mediated by their therapeutic antibodies. Therefore, targeting pro-tumorous exosomes may achieve antitumor effect supplementary to existing therapies. Exosome, itself natural liposome-like structure, allows it to be a potential drug delivery tool.Immune checkpoints are variegated stimulatory and inhibitory signals that are fundamental in immune homeostasis. The regulative molecules for immune checkpoints include programmed cell death protein 1 (PD1), programmed death-ligand 1 or 2 (PD-L1 or PD-L2), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and so on. While the immune checkpoint molecules have gained soaring attention in recent years, the trafficking of them has been rarely studied. Since all of the discovered immune checkpoint molecules are transmembrane domain (TMD) proteins, they share similar pathophysiological characteristics which make studies about their trafficking and associated disorders resembled. PD-L1 is one of the most classic immune checkpoint molecules, and anti-PD1 monoantibodies have shown promising immunotherapeutic effects. PD-L1 trafficking has been particularly studied, the key regulators of which include metformin, chemokine-like factor-like MARVEL transmembrane domain-containing family member (CMTM), Huntingtin-interacting protein 1-related (HIP1R), exosomes, ALIX, polyIC, and various post-translational modifications. Here, we focus on the checkpoints under traffic control, counting PD-L1, CTLA-4, lymphocyte-activation gene 3 (LAG-3), killer immunoglobulin-like receptors (KIRs), CD70, CD94, and attempt to shed light on the potentials of drug targets based on these findings and look forward to further studies in combinatorial therapeutic regimens in the meantime.It is well established that palmitoylation plays a key role in the regulation of immune checkpoints, but the technical challenges in detecting protein palmitoylation have significantly prohibited further researches in this field. Till now, different approaches have been proposed, such as mutagenesis, antibody-based methods, bioinformatic prediction, "palmitate-centric" approaches, and "cysteine-centric" approaches. Of specific importance, high-throughput methods that allow the unbiased discovery of palmitoylation in the whole proteome should be further improved and employed. This chapter will summarize the methodological progresses for detecting protein palmitoylation, aiming to facilitate future researches in the lipid modification of immune checkpoint proteins.The ligands and receptors in immune checkpoint signaling are typically transmembrane proteins, which may be regulated by palmitoylation as a reversible lipid modification. Our recent work demonstrated that palmitoylation reduces the lysosomal degradation of PD-L1 trafficking and may present a new therapeutic target. To facilitate future investigations on palmitoylation and immune checkpoints, here we summarize the molecular roles of palmitoylation on protein stability, trafficking, membrane association, and protein-protein interaction. The biological effects of palmitoylation are exemplified by well-studied substrates such as Ras, EGFR, and Wnt proteins. Finally, the strategies for targeting protein palmitoylation are discussed to facilitate future translational studies.Checkpoint signaling involves a variety of upstream and downstream factors that participate in the regulation of checkpoint expression, activation, and degradation. During the process, phosphorylation plays a critical role. Phosphorylation is one of the most well-documented post-translational modifications of proteins. Of note, the importance of phosphorylation has been emphasized in aspects of cell activities, including proliferation, metabolism, and differentiation. Here we summarize how phosphorylation of specific molecules affects the immune activities with preference in tumor immunity. Of course, immune checkpoints are given extra attention in this book. There are many common pathways that are involved in signaling of different checkpoints. Some of them are integrated and presented as common activities in the early part of this chapter, especially those associated with PD-1/PD-L1 and CTLA-4, because investigations concerning them are particularly abundant and variant. Their distinct regulation is supplementarily discussed in their respective section. As for checkpoints that are so far not well explored, their related phosphorylation modulations are listed separately in the later part. We hope to provide a clear and systematic view of the phosphorylation-modulated immune signaling.
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