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- Zhou, H, et al.
(author)
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Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals
- 2018
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:11, s. 1086-
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Journal article (peer-reviewed)abstract
- Oncolytic peptides and peptidomimetics are being optimized for the treatment of cancer by selecting agents with high cytotoxic potential to kill a maximum of tumor cells as well as the capacity to trigger anticancer immune responses and hence to achieve long-term effects beyond therapeutic discontinuation. Here, we report on the characterization of two novel oncolytic peptides, DTT-205 and DTT-304 that both selectively enrich in the lysosomal compartment of cancer cells yet differ to some extent in their cytotoxic mode of action. While DTT-304 can trigger the aggregation of RIP3 in ripoptosomes, coupled to the phosphorylation of MLKL by RIP3, DTT-205 fails to activate RIP3. Accordingly, knockout of either RIP3 or MLKL caused partial resistance against cell killing by DTT-304 but not DTT-205. In contrast, both agents shared common features in other aspects of pro-death signaling in the sense that their cytotoxic effects were strongly inhibited by both serum and antioxidants, partially reduced by lysosomal inhibition with bafilomycin A1 or double knockout of Bax and Bak, yet totally refractory to caspase inhibition. Both DTT-304 and DTT-205 caused the exposure of calreticulin at the cell surface, as well as the release of HMGB1 from the cells. Mice bearing established subcutaneous cancers could be cured by local injection of DTT-205 or DTT-304, and this effect depended on T lymphocytes, as it led to the establishment of a long-term memory response against tumor-associated antigens. Thus, mice that had been cured from cancer by the administration of DTT compounds were refractory against rechallenge with the same cancer type several months after the disappearance of the primary lesion. In summary, DTT-205 and DTT-304 both have the capacity to induce immunotherapeutic oncolysis.
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- Zhou, H, et al.
(author)
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The oncolytic peptide LTX-315 triggers immunogenic cell death
- 2016
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 7, s. e2134-
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Journal article (peer-reviewed)abstract
- LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.
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- Bezu, L, et al.
(author)
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Immunological Effects of Epigenetic Modifiers
- 2019
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In: Cancers. - : MDPI AG. - 2072-6694. ; 11:12
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Journal article (peer-reviewed)abstract
- Epigenetic alterations are associated with major pathologies including cancer. Epigenetic dysregulation, such as aberrant histone acetylation, altered DNA methylation, or modified chromatin organization, contribute to oncogenesis by inactivating tumor suppressor genes and activating oncogenic pathways. Targeting epigenetic cancer hallmarks can be harnessed as an immunotherapeutic strategy, exemplified by the use of pharmacological inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) that can result in the release from the tumor of danger-associated molecular patterns (DAMPs) on one hand and can (re-)activate the expression of tumor-associated antigens on the other hand. This finding suggests that epigenetic modifiers and more specifically the DNA methylation status may change the interaction of chromatin with chaperon proteins including HMGB1, thereby contributing to the antitumor immune response. In this review, we detail how epigenetic modifiers can be used for stimulating therapeutically relevant anticancer immunity when used as stand-alone treatments or in combination with established immunotherapies.
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- Castoldi, F, et al.
(author)
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Autophagy-mediated metabolic effects of aspirin
- 2020
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In: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 6:1, s. 129-
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Journal article (peer-reviewed)abstract
- Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b−/− or Bcln1+/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
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