Mechanisms of natural killer cell-mediated cellular cytotoxicity

Prager, Isabel; Watzl, Carsten

doi:10.1002/jlb.mr0718-269r

Cited by 354 publications

(325 citation statements)

References 166 publications

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“…NK cells have a wide array of inhibitory and stimulatory receptors on their cell surface that are used for immune surveillance. Upon activation, NK cells show potent cytolytic activity in response to infected or transformed cells by releasing cytotoxic perforin and granzyme and activating apoptotic pathways in target cells through the production of TNFα or via direct cell-cell contact through activation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FASL) pathways [70,71]. Recent work has demonstrated important roles of PARP-1 in NK cell biology.…”

Section: Role Of Parp-1 and Parp-2 In The Cellular Components Of Thementioning

confidence: 99%

“…Moreover, the PARP inhibitor Niraparib has been shown to enhance type I interferon signaling and T cell infiltration in the tumor and improve the therapeutic effect of anti-PD-1 [94]. NK cells can kill cancer cells by inducing death receptor-mediated apoptosis through the expression of FasL or TRAIL [71]. PARP inhibitors have been shown to sensitize cancer cells to death receptor-mediated apoptosis by upregulating death receptor surface expression [95,96] (Figure 4).…”

Section: Parp Inhibitors As Immunomodulatory Agentsmentioning

confidence: 99%

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Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

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Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which posttranslationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.

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Section: Role Of Parp-1 and Parp-2 In The Cellular Components Of Thementioning

confidence: 99%

Section: Parp Inhibitors As Immunomodulatory Agentsmentioning

confidence: 99%

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Yélamos

Moreno-Lama

Jimeno

et al. 2020

Cancers

View full text Add to dashboard Cite

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“…As we did not observe correlation between the expression of well-known NK cell-interacting surface ligands with the sensitivity of different target cell lines to distinct NK 8 cell cytotoxic modes, we next investigated the functional involvement of the key inhibitory and activating receptors on NK cell surface, as the target specificity could be conferred by surface ligands not in the profiling panel as discussed above. The NK cell receptors that we examined included two types of inhibitory receptors, KIRs and NKG2A (CD94), and three activating receptors important for cancer target recognition, including NKG2D (CD314), DNAM-1 (CD226) and NKp46 (CD335) [11,21]. Specifically, we used neutralizing antibodies to block individual receptors or combination of the receptors and then compared the extent and kinetics of target cell death via the three cytotoxic modes with those under the control condition (i.e., no receptor blocking).…”

Section: Target Dependence Of Nk Cell Cytotoxicity On Inhibitory Andmentioning

confidence: 99%

“…The Rac inhibitor, NSC23766, was from SelleckChem and used at 120 M for MCF7 and 50 M for SMMC-7721. Cells were pre-treated with either Y27632 for 1 hour or NSC23766 for [5][6][7][8][9][10][11][12] hours before experiments. The inhibitor of vacuolar type ATPase (V-ATPase), Concanamycin A, was from Santa Cruz Biotechnology.…”

Section: Chemicals and Neutralizing Antibodiesmentioning

confidence: 99%

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Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis

Zhu

Xie

Shi

2019

Preprint

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Natural Killer (NK) cells play a key role in eliminating virus-infected cells and cancer cells.Although molecular machineries mediating their activity and specificity have been extensively studied, our understanding of the determinants that govern the differential cytotoxicity of NK cells against distinct epithelial cell targets is still limited. By employing a live-cell FRET reporter and quantitative single cell imaging, we characterized the dynamic phenotypes and rate-limiting kinetics of a panel of normal and epithelial cancer cells to killing by primary human NK cells. We uncovered intriguing target-dependent variability in their sensitivity to three distinct NK cell cytotoxic modes mediated by granzyme, death ligand and the largely unexplored necrosis. While NK-target cell interaction via known inhibitory and activating receptors, in particular the KIRs, largely determined the overall cytotoxic activity, we found the variable sensitivity to distinct NK cell cytotoxic modes was not regulated by individual receptors. Instead, plasma membrane dynamics driven by blebs and/or lamellipodia appeared to control the induction of different cytotoxic modes in a target-specific manner, particularly promoting necrotic killing. Our results point to modulating the membrane dynamics of epithelial cell targets as a viable strategy to control the degree, timing and inflammatory consequences of NK cell killing.

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Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway

et al. 2021

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Invariant natural killer T (iNKT) cells are lipid-specific T lymphocytes endowed with cytotoxic activities and are thus considered important in antitumor immunity. While several studies have demonstrated iNKT cell cytotoxicity against different tumors, very little is known about their cellkilling activities in human colorectal cancer (CRC). Our aim was to assess whether human iNKT cells are cytotoxic against colon cancer cells and the mechanisms underlying this activity. For this purpose, we generated stable iNKT cell lines from peripheral blood and colon specimens and used NK-92 and peripheral blood natural killer cells as cell-mediated cytotoxicity controls. In vitro cytotoxicity was assessed using a panel of well-characterized human CRC cell lines, and the cellular requirements for iNKT cell cytotoxic functions were evaluated. We demonstrated that both intestinal and circulating iNKT cells were cytotoxic against the entire panel of CRC lines, as well as against freshly isolated patient-derived colonic epithelial cancer cells. Perforin and/or granzyme inhibition impaired iNKT cell cytotoxicity, whereas T-cell receptor (TCR) signaling was a less stringent requirement for efficient killing. This study is the first evidence of tissue-derived iNKT cell cytotoxic activity in humans, as it shows that iNKT cells depend on the perforin-granzyme pathway and both adaptive and innate signal recognition for proper elimination of colon cancer cells.

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Mechanisms of natural killer cell-mediated cellular cytotoxicity

Cited by 354 publications

References 166 publications

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis

Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway

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