Small-Molecule Drugs in Immunotherapy.

Immunotherapy has been increasingly used in the treatment of cancer. Compared with chemotherapy, immunotherapy relies on the autoimmune system with fewer side effects. Small molecule immune-oncological medicines usually have good bioavailability, higher tissue and tumor permeability, and a reasonable half-life. In this work, we summarize the current advances in the field of small molecule approaches in tumor immunology, including small molecules in clinical trials and preclinical studies, containing PD1/PD-L1 small molecule inhibitors, IDO inhibitor, STING activators, RORγt agonists, TGF-ß inhibitors, etc. PD-1/DP-L1 is the most attractive target at present. Some small molecule drugs are being in clinical trial studies. Among them, CA-170 has attracted much attention as an oral small molecule drug. IDO is another popular target after PD-1/PDL1. The dual IDO and PD-1 inhibitor can improve the low response of PD-1 and has a good synergistic effect. STING is a protein that occurs naturally in the human body and can enhance the body's immunity. RORγt is mainly expressed in cells of the immune system. It promotes the differentiation of Th17 cells and produces the key factor IL-17, which plays a key role in the development of autoimmune diseases. TGFß signaling exhibits potent immunosuppressive activity on the coordinate innate and adaptive immunity, impairing the antitumor potential of innate immune cells in the tumor microenvironment. It is worth mentioning that immunotherapy drugs can often achieve better effects when used in combination, which will help defeat cancer.

Pulmonary Delivery of Levamisole Nanoparticles as an Immunomodulator Affecting Th and a Potential ADAM10 Inhibitor to Ameliorate Severe Allergic Asthma.

Asthma is a common chronic lung disease without absolute treatment, and hypersensitivity reactions and type 2 immune responses are responsible for asthma pathophysiology. ADAM10 as a metalloproteinase transmembrane protein is critical for development of Th2 responses, and levamisole as an anthelmintic drug has immunomodulatory effects, which not only regulates ADAM10 activity but also can suppress the bone marrow and neutrophil production. Therefore, in the present study, nanoparticles were used as a levamisole delivery system to reduce bone marrow suppression, and the immunomodulatory and ADAM10 inhibitory effects of levamisole were studied in allergic asthma. Asthmatic mice were treated with PLGA-levamisole nanoparticles. Then, AHR, BALF, and blood cell counts, levels of the IgG1 subclass, total and OVA-specific IgE, IL2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-25, IL-33, INF-γ, and TNF-α, gene expression of FoxP3, T-bet, RORγt, PU.1, GATA3, FcεRII, CysLT1R, eotaxin, and ADAM10, and lung histopathology were evaluated. PLGA-LMHCl with considered characteristics could control airway hyper-responsiveness, eosinophils in the BALF, levels of immunoglobulins, Th2-, Th9-, and Th17-derived cytokines and pivotal genes, eosinophilic inflammation, hyperplasia of the goblet cell, and hyperproduction of mucus and could increase Th1- and Treg-derived cytokines and also pivotal genes. It could also modulate the ADAM10 activity and had no effect on the number of neutrophils in the bloodstream. The novel safe nanodrug had no side effect on the bone marrow to produce neutrophils and could control the allegro-immuno-inflammatory response of asthma.

The Functional Stability of FOXP3 and RORγt in Treg and Th17 and Their Therapeutic Applications.

The balance of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and effector T cells plays a key role in maintaining immune homeostasis, while the imbalance of them is related to many inflammatory diseases in both human and mice. Here we discuss about the plasticity of Tregs and Th17 cells, and the related human diseases resulted from the imbalance of them. Further, we will focus on the mechanisms regulating the plasticity between Tregs and Th17 cells and the potential therapeutic strategies by targeting regulators of the expression and activity of FOXP3 and RORγt or regulators of Treg/Th17 balance in autoimmune diseases, allergy, infection, and cancer.