Immunogenic cell stress and death

Kroemer, Guido; Galassi, Claudia; Zitvogel, Laurence; Galluzzi, Lorenzo

doi:10.1038/s41590-022-01132-2

Cited by 518 publications

(439 citation statements)

References 255 publications

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“…Immunogenic cell death inducers have been reported to induce apoptosis, necroptosis or ferroptosis and to frequently inhibit DNA-to-RNA transcription. 54 Further results showed z-VAD-fmk and ferrostatin, which are inhibitors of pro-apoptotic caspases and ferroptosis, respectively failed to inhibit tumor cell death induced by local anesthetics. In contrast, necrostatin-1 attenuated the cytotoxic effects of lidocaine on tumor cells suggesting local anesthetics induce necroptosis ( online supplemental figure S8D ).…”

Section: Resultsmentioning

confidence: 98%

Local anesthetics elicit immune-dependent anticancer effects

Bezu

Chuang

Sauvat

et al. 2022

J Immunother Cancer

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BackgroundRetrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice.ResultsIn vitro, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. In vivo, locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics.ConclusionAltogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.

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Section: Resultsmentioning

confidence: 98%

Local anesthetics elicit immune-dependent anticancer effects

Bezu

Chuang

Sauvat

et al. 2022

J Immunother Cancer

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“…ICD is a critical event in tumor immunotherapy by triggering the activation of anti-tumor immunity, and facilitates the tumor suppression effect (10). Cell death can induce immune tolerance or immunogenicity, depending on whether a release of damage-associated molecular patterns (DAMPs) occurs during cell death (11).…”

Section: Resultsmentioning

confidence: 99%

“…These results demonstrated that RiboPROTAC mediated PCNA degradation resulted in potent cytotoxicity for cancer cells in vitro. ICD is considered to exert dual functions in tumor therapy, including a notable reduction of tumor burden by inducing tumor cell death, and a primming of tumor immunity to arouse systemic T cell cytotoxicity for tumor elimination (10). Accumulated pre-clinical and clinical studies have revealed that ICD induction is a crucial and promising strategy in developing anti-tumor therapeutics or clinical therapeutic methods (24, 25).…”

Section: Discussionmentioning

confidence: 99%

Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets

Yang¹,

Sun²,

Zhu³

et al. 2022

Preprint

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Although proteolysis targeting chimera (PROTAC) technology that hijacking the ubiquitin-proteasome system (UPS) to artificially degrade protein is an emerging promising technology for many undruggable targets, it still faces several challenges, such as the difficulty to select high specificity molecule to protein of interest (POI), and only few of the E3-ligase are suitable for PROTAC mediated protein degradation. Protein-based PROTAC, termed BioPROTAC, owns the advantage of specificity but lacks membrane permeability. Here, we develop a new targeted protein degrading platform, which we termed RiboPROTAC, by encoding BioPROTAC protein degraders with circular mRNA (cmRNA) and delivering intracellularly. In this way, intracellular protein GFP and nuclear protein PCNA were successfully degraded. For PCNA targeting, not only the level of target protein is strongly decreased, but also the cell function related is strongly interfered, such as cell proliferation, apoptosis, as well as the cell cycle. What is more, for the first time, we observed that degrading PCNA with RiboPROTAC causes immunogenic cell death (ICD), although not strong, but was verified in vivo. Importantly, our in vivo results demonstrated that cmRNA encoded PCNA degrader exhibited significant tumor suppression effect, thus we provide the first proof of concept for the application of RiboPROTAC as potential mRNA therapeutic. We consider that RiboPROTAC is a new and superior PROTAC technology for targeting the undruggable targets.

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“…In addition, apoptotic cells display a variety of "find me" and "eat me" signals that aid in the efficient recognition and clearance of cell corpses by phagocytic cells including macrophages [3][4][5]. These events reduce the risk of cellular contents being released by dying cells in order to limit the induction of acute inflammatory and adaptive immune responses over time [6].…”

Section: Introductionmentioning

confidence: 99%

Immunogenic cell death in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors

Naylor

Julian

Watson-Bryce

et al. 2022

Preprint

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The characteristic changes in morphology during apoptosis help facilitate "immunologically-silent" cell death by limiting the release of cellular contents and enabling efficient clearance of apoptotic cell bodies. Caspase-mediated cleavage of the ROCK1 protein kinase results in its constitutive activation, which drives the rapid and forceful contraction of apoptotic cells. We previously showed in Julian et al. that when ROCK1 was mutated to render it caspase-resistant, there was greater liver damage and neutrophil recruitment after acute treatment with the hepatotoxin diethylnitrosamine (DEN). We now show that acute DEN-induced liver damage resulted in greater induction of pro-inflammatory cytokines/chemokines, indicative of immunogenic cell death (ICD), in mice expressing non-cleavable ROCK1 (ROCK1nc). Hepatocellular carcinoma (HCC) tumours in ROCK1nc mice had higher grade steatosis, and more neutrophils and CD8+ T cells relative to mice expressing wild-type ROCK1 (ROCK1wt), indicating that spontaneous tumour cell death also was more immunogenic. Since the induction of ICD has been proposed to be tumour-suppressive, the effects of two structurally distinct pharmacological ROCK inhibitors on HCC tumours was examined. Both fasudil and AT13148 significantly decreased tumour numbers and area, but neither treatment resulted in greater numbers of neutrophils or CD8+ T cells to be recruited. In the context of acute DEN-induced liver damage, AT13148 reduced circulating platelet and lymphocyte numbers, and inhibited the recruitment of dendritic, natural killer and CD8+ T cells to livers. These observations indicate that there is an important role for ROCK1 cleavage to limit immunogenic cell death which was not replicated by systemic administration of pharmacological ROCK inhibitors. As a result, adjuvant administration of ROCK inhibitors with cancer therapeutics would be unlikely to result in therapeutic benefit by inducing ICD to increase anti-tumour immune responses.

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Immunogenic cell stress and death

Cited by 518 publications

References 255 publications

Local anesthetics elicit immune-dependent anticancer effects

Local anesthetics elicit immune-dependent anticancer effects

Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets

Immunogenic cell death in mice expressing caspase-resistant ROCK1 is not replicated by ROCK inhibitors

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