Abstract
BackgroundNatural killer (NK) cells play an important role in cancer immunosurveillance and therapy. However, the target selectivity of NK cell activity is still poorly understood.ResultsHere, we used live-cell reporters to unravel differential epithelial cancer target killing by primary human NK cells. We found highly variable fractions of killing by distinct NK cell cytotoxic modes that were not determined by NK ligand expression. Rather, epithelial plasma membrane dynamics driven by ROCK-mediated blebs and/or Rac1-mediated lamellipodia promoted necrotic mode in preference to the apoptotic mode of killing. Inhibition of granzyme B and key necroptosis regulators RIP1, RIP3, and MLKL significantly attenuated the necrotic killing, revealing a novel NK cell cytotoxic pathway by granzyme-induced necroptosis that conferred target selectivity.ConclusionsOur results not only elucidate a new NK cell effector mechanism but also suggest that tissue microenvironment and oncogenic signaling pathways that promote membrane dynamics, e.g., Rac1 and Rho/ROCK, could be exploited to enhance proinflammatory NK cell killing.
Highlights
Natural killer (NK) cells play an important role in cancer immunosurveillance and therapy
Target cell-type dependence of NK cell cytotoxicity To investigate the mechanisms underlying the differential activity of NK cells on distinct targets, we chose a panel of human epithelial cell lines that exhibited variable sensitivity to primary NK cell killing, including one normal cell line, LO2, and four cancer cell lines, i.e., HeLa, SMMC-7721, MCF7, and U-2 OS
The GrzmB-Förster resonance energy transfer (FRET) reporter consists of a cyan (CFP, donor) and yellow (YFP, receptor) fluorescent protein linked by a peptide substrate specific to granzyme B, i.e., VGPDFGR
Summary
Natural killer (NK) cells play an important role in cancer immunosurveillance and therapy. Natural killer (NK) cells detect and kill virus-infected cells and cancer cells and are considered a promising immunotherapeutic target [1, 2]. Harnessing and stimulating the direct cytotoxic activity of NK cells has attracted growing interest in the recent development of cancer immunotherapy, as diverse tumor cell types showed susceptibility to NK cell killing and targeted therapy and immune checkpoint inhibitors may act in part via triggering NK cell response [3,4,5]. The variable sensitivity of cancer cells to killing by NK cells can be broken into two distinct processes, i.e., detection of abnormal cancer targets and selection of killing mechanism from the NK cell arsenal, which becomes important if the cancer target is resistant to one or more killing pathways. The major inhibitory receptors on NK cells are killer cell immunoglobulin-like receptors (KIRs), which interact with major histocompatibility complex I (MHCI) molecules of the target cells, leading to NK cell “self-
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
