Targeting TNF/TNFR Signaling Pathways

Members of the tumor necrosis factor receptor superfamily (TNFRSF) can be specifically activated to induce death of some cancer cells or to stimulate proliferation of immune cells. There are genuine needs for in-depth understanding of the mechanism by which these receptors are activated, as many of them are targets for immunotherapy. Recently, a series of studies have indicated that activation of receptors by antibodies is not as simple as concentrating the receptors in the cell membrane by multivalent engagement of the receptor ectodomains, as there appear to be specific conformational and clustering arrangement of the receptors that strongly influence signaling and the mode of ligand induced receptor clustering and activation can vary significantly among different members of the TNFRSF. For example, some receptors depend strongly on clustered ligand engagement to cluster and activate while others can cluster on their own upon binding to soluble ligands. Higher order clustering of receptors such as TNFR1 are mostly mediated by self-association of the extracellular region, but in some cases such as DR5, receptor clustering can be driven purely by the transmembrane domain when autoinhibition by the ectodomain is released. Further, we believe different members of the TNFRSF have different mechanism of autoinhibition in the absence of ligand. Hence, therapeutic targeting of the signaling pathways of the TNFRSF needs to be tailored to each member of the receptor family, and this would require in-depth understanding of the various mechanism of receptor autoinhibition and activation adopted by each of the TNFR family members.

The aim of the current Research Topic is to assemble new data and novel strategies for therapeutic targeting of the receptors in the TNFRSF as well as the latest findings about the mechanism of receptor autoinhibition and activation. The new collection of articles will expand our knowledge of the various ways in which the receptors in the TNFRSF can be modulated for therapeutic application, stimulate the discussion of new strategies for developing biologics and small molecule drugs, and advance our understanding of autoinhibition and activation of the therapeutically important members of the TNFRSF.

The subtopics include but are not limited to

• Mechanism by which the receptor signaling can be targeted for members of the TNFRSF
• Extrinsic targeting of receptors by antibodies and small molecules
• Targeting the intracellular pathways
• Implication of receptor preligand arrangement to antibody/small molecule development
• Clinical aspects of modulating TNF receptors

We welcome submissions of original research articles, reviews, case reports, empirical studies, and opinions.