The use of supercytokines, immunocytokines, engager cytokines, and other synthetic cytokines in immunotherapy

Cytokines exert powerful immunomodulatory effects that are critical to physiology and pathology in humans.The application of natural cytokines in clinical studies has not been clearly established,and there are often problems associated with toxicity or lack of efficacy.The key reasons can be attributed to the pleiotropy of cytokine receptors and undesired activation of off-target cells.With a deeper understanding of the structural principles and functional signals of cytokine-receptor interactions,artificial modification of cytokine signaling through protein engineering and synthetic immunology has become an increasingly feasible and powerful approach.Engineered cytokines are designed to selectively target cells.Herein,the theoretical and experimental evidence of cytokine engineering is reviewed,and the“supercytokines”resulting from structural enhancement and the“immunocytokines”generated by antibody fusion are described.Finally,the“engager cytokines”formed by the crosslinking of cytokines and bispecific immune engagers and other synthetic cytokines formed by nonnatural analogs are also discussed.

CD226:a potent driver of antitumor immunity that needs to be maintained

Inhibitory receptors expressed on the immune cell surface have emerged as checkpoint molecules that could be therapeutically targeted for tumor immunotherapy.However,antitumor immunity mediated by checkpoint blockade depends on optimal recognition of tumor cells through the activation of receptors on antitumor effector immune cells,such as CD8^(+)T cells and NK cells.Therefore,sufficient and maintained expression levels of activating receptors on these effector immune cells are essential for antitumor immunity and checkpoint blockade immunotherapy.

NK cell dysfunction in patients with COVID-19

A substantial proportion of patients with coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection might develop severe pneumonia and fibrotic lung damage at later stages after the infection.Efficient antiviral immunity and prevention of fibrosis progression are critical for COVID-19 control.Natural killer(NK)cells,whose targeting strategies have already provided therapeutic benefits in immunotherapy against tumors,are innate lymphocytes that also play an important role in antiviral immunity.In support of targeting NK cells in patients with COVID-19,Krämer et al.recently provided evidence that NK cells display anti-SARS-CoV-2 activity[1].They showed that purified peripheral NK cells from healthy individuals reduce viral protein levels in cocultured SARS-CoV-2-infected cells.

Increased expression of adenosine A3 receptor in tumor-infiltrating natural killer cells

Checkpoint blockade on lymphocyte surfaces has revolutionizedcancer treatment.ln particular,blockade of programmed celldeath protein-1 by therapeutic antibodies is remarkably effectiveto reactivate T cells for the treatment of several cancer types.^(1,2).lmmune checkpoint inhibitors that promote natural killer(NK)celleffector function have also recently demonstrated significantefficacy.^(3,4)Notably however,one of the main challenges of theseclinical immunotherapies is that the majority of patients areresistant to immune checkpoint inhibitors^(5).One practicalapproach to address this is identifying novel molecular targetsand manipulating them to enhance antitumor immunity.