Granzyme B–Activated p53 Interacts with Bcl-2 To Promote Cytotoxic Lymphocyte–Mediated Apoptosis

Safta, Thouraya Ben; Ziani, Linda; Favre, Loëtitia; Lamendour, Lucille; Gros, Gwendoline; Mami‐Chouaib, Fathia; Martinvalet, Denis; Chouaı̈b, Salem; Thiery, Jérôme

doi:10.4049/jimmunol.1401978

Cited by 45 publications

(42 citation statements)

References 54 publications

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“…20,37–39 Moreover, introduction of p53 into tumor cells was shown to enhance induction of apoptosis following exposure to CTL-mediated cytotoxic insults 39 and p53 accumulation in tumor cells is an indispensable component in the GzmB-induced apoptotic signaling pathway. 41,42 …”

Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…Cytotoxicity was measured by a 4 hr chromium release assay as previously described [63]. Experiments were performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion

et al. 2017

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Cancer-associated fibroblasts (CAFs) play a central role in the complex process of tumor-stroma interaction and promote tumor growth. Emerging evidences also suggest that these fibroblasts are involved in the alteration of the anti-tumor immune response by impacting several immune cell populations, especially through their secretion of pro-inflammatory and immunosuppressive factors in the tumor microenvironment. However, the underlying immuno-modulating mechanisms triggered by these fibroblasts are still only partially defined. In this study, we provide evidence that melanoma-associated fibroblasts decrease the susceptibility of melanoma tumor cells to NK-mediated lysis through the secretion of active matrix metalloproteinases. This secretion reduces the expression of the two NKG2D ligands, MICA/B, at the surface of tumor cells and consequently decreases the NKG2D-dependent cytotoxic activity of NK cells against melanoma tumor cells. Together, our data demonstrate that the modification of tumor cell susceptibility to killer cells is an important determinant of the anti-tumor immune response alteration triggered by CAFs.

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“…Cancer cells may again exploit various strategies to compensate this loss such as upregulation of the nonclassical MHC class I proteins HLA‐G (Carosella et al ., ) and HLA‐E (Braud et al ., ), able to restrain NK activity through KIRs and CD94/NKG2A, respectively. There is also evidence in some cancer cells for an increase in resistance to perforin/granzyme B‐mediated cell death by immune cells (Ben Safta et al ., ), reduction in cell surface MHC class I‐related chain (MIC) proteins, MICA and MICB, and UL16 binding proteins, ligands for NK‐activating receptor‐activating NKG2D (Malladi et al ., ). Furthermore, the production by certain cancer cells of soluble forms of MICs could act as a decoy for NK cells while promoting degradation of NKG2D (Groh et al ., ; Raffaghello et al ., ).…”

Section: Immune Resistance To Nk Cellsmentioning

confidence: 99%

New insights into the role of EMT in tumor immune escape

et al. 2017

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Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial‐mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments.

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Granzyme B–Activated p53 Interacts with Bcl-2 To Promote Cytotoxic Lymphocyte–Mediated Apoptosis

Cited by 45 publications

References 54 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion

New insights into the role of EMT in tumor immune escape

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