Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.

ABSTRACT: 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. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. 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. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transfer

SUBMITTER: Dhar P 

PROVIDER: S-EPMC8298432 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature