Abstract
Understanding and targeting Notch signaling effectively has long been valued in the field of cancer and other immune disorders. Here, we discuss key discoveries at the intersection of Notch signaling, cancer and immunology. While there is a plethora of Notch targeting agents tested in vitro, in vivo and in clinic, undesirable off-target effects and therapy-related toxicities have been significant obstacles. We make a case for the clinical application of ligand-derived and affinity modifying compounds as novel therapeutic agents and discuss major research findings with an emphasis on Notch ligand-specific modulation of immune responses.
Highlights
Notch signaling plays a variety of physiological roles including, but not limited to, cell proliferation, cell fate decisions, cellular differentiation and angiogenesis [1]
Notch1 and Notch2 were found to be downregulated in tumor infiltrating T cells but not in splenic T cells of tumor-bearing mice [29]. This attenuation of infiltrating T cell responses was driven by Jag1/2 expressed by immunosuppressive myeloid-derived suppressor cells (MDSCs) which could be overcome by ectopic expression of Notch1 intracellular domain (N1ICD) in antigen specific T cells, indicating that the tumor microenvironment (TME) is programmed with mechanisms to suppress Notch signaling and evade T cellmediated tumor cell death
While several studies demonstrated the involvement of Notch signaling in driving effector and helper T cell responses, the precise regulatory mechanisms behind cell surface expression of Notch ligands and receptors are only partly known
Summary
Notch signaling plays a variety of physiological roles including, but not limited to, cell proliferation, cell fate decisions, cellular differentiation and angiogenesis [1]. We report findings that revealed the varied effects of Notch signaling in immune compartments driving T cell development, activation, differentiation, and regulation of effector immune responses. This attenuation of infiltrating T cell responses was driven by Jag1/2 expressed by immunosuppressive myeloid-derived suppressor cells (MDSCs) which could be overcome by ectopic expression of Notch1 intracellular domain (N1ICD) in antigen specific T cells, indicating that the TME is programmed with mechanisms to suppress Notch signaling and evade T cellmediated tumor cell death.
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