Human NKG2D Ligand Regulation of NK Cell Functions and     Metabolism: From Molecular Mechanisms to Therapeutics

Dhar, Payal

doi:https://doi.org/10.21985/n2-dgdr-se80

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Human NKG2D Ligand Regulation of NK Cell Functions and Metabolism: From Molecular Mechanisms to Therapeutics

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Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. NKG2D/NKG2DL pathway is very well recognized as an effective immune axis in tumor immunosurveillance. Abundant evidence from experimental preclinical animal models as well as clinical studies have established the protective role of NKG2D and its ligands in tumor immunity. Despite this, inability to distinguish between the soluble and membrane restricted NKG2D ligands led to conflicting clinical findings and controversies in the literature in the past, questioning their value as prognostic biomarkers. We have demonstrated that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cells to secrete pro-tumorigenic cytokines with diminished cytotoxicity. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Additionally, metabolic reprograming is known to be a critical regulator of immune cell functions and survival. How sMIC influences NK cell metabolism is not known. We demonstrated that sMIC induces metabolic alterations in NK cells which are associated with their impaired anti-tumor functionality. Targeting sMIC-mediated perturbations in NK cell metabolism promotes functions of intra-tumoral NK cells. We demonstrated that antibody clearing sMIC restores NK cells to a normal cytotoxic effector functional and metabolic state. Our findings uncover new mechanisms that could instruct NK cells to a dysfunctional state in response to cues in the tumor microenvironment and provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy.

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