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1.
Oncoimmunology ; 10(1): 2005859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858731

RESUMO

High mobility group B1 (HMGB1) is a protein that is released from dying cancer cells in the context of immunogenic cell death (ICD). A recent study performed on patients with head and neck squamous cell carcinomas (HNSCC) reports that a chemoradiotherapy-induced increase in circulating HMGB1 levels predicts favorable outcome, echoing prior studies on neoadjuvant treatment of breast and rectal cancer in which the dynamics of HMGB1 plasma levels also have prognostic value. Hence, a therapy-induced rise in HMGB1 may be interpreted as a clinical sign of ICD and therapeutic response.

2.
Cell Death Dis ; 12(11): 1039, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725331

RESUMO

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of ß-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca2+ stores and store-operated Ca2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.

3.
Oncoimmunology ; 10(1): 1996686, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745770

RESUMO

Sequential combination of immunogenic cell death (ICD)-induced interventions with subsequent immunotherapy has shown efficacy in preclinical models and clinical evaluation. Recently, a clinical trial enrolling small cell lung cancer patients treated with amrubicin together with PD-1 blockade confirmed the notion that ICD sensitizes tumors to immune checkpoint inhibitors.

5.
Circulation ; 144(22): 1795-1817, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34843394

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD+-degrading enzymes, external supplementation of NAD+ precursors, and transgenic overexpression of NAD+-generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD+ pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD+ replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD+ improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD+ metabolism, comparatively evaluate distinct NAD+ precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD+ replenishment or supraphysiological NAD+ elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD+ precursors. The development of such NAD+-centered treatments will rely on technological and conceptual progress on the fine regulation of NAD+ metabolism.

6.
Semin Cancer Biol ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34624451

RESUMO

Besides tumor cell-intrinsic oncogenic pathways, host and environmental factors have a major impact on cancer immunosurveillance and the efficacy of immunotherapeutics. Several modalities of anticancer treatments including immunogenic chemotherapies and immune checkpoint inhibitors lose their efficacy in patients treated with broad-spectrum antibiotics, pointing to a key role for the gut microbiota. The complex interactions between intestinal microbes, gut immunity and anti-tumor responses constitute an emerging field of investigation. In this work, we revise key primary literature, with an emphasis on recent mechanistic insights, unraveling the interplay between the immunosurveillance of colon cancers and ileal factors including the local microbiota, tissue architecture and immune system.

7.
Oncoimmunology ; 10(1): 1984677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34676147

RESUMO

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re)activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radiotherapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity.


Assuntos
Neoplasias , Vírus Oncolíticos , Anticorpos Monoclonais/uso terapêutico , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias/terapia
9.
Cell Death Dis ; 12(11): 978, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675191

RESUMO

Colorectal cancers (CRC) can be classified into four consensus molecular subtypes (CMS), among which CMS1 has the best prognosis, contrasting with CMS4 that has the worst outcome. CMS4 CRC is notoriously resistant against therapeutic interventions, as demonstrated by preclinical studies and retrospective clinical observations. Here, we report the finding that two clinically employed agents, everolimus (EVE) and plicamycin (PLI), efficiently target the prototypic CMS4 cell line MDST8. As compared to the prototypic CMS1 cell line LoVo, MDST8 cells treated with EVE or PLI demonstrated stronger cytostatic and cytotoxic effects, increased signs of apoptosis and autophagy, as well as a more pronounced inhibition of DNA-to-RNA transcription and RNA-to-protein translation. Moreover, nontoxic doses of EVE and PLI induced the shrinkage of MDST8 tumors in mice, yet had only minor tumor growth-reducing effects on LoVo tumors. Altogether, these results suggest that EVE and PLI should be evaluated for their clinical activity against CMS4 CRC.

10.
Blood Cancer Discov ; 2(5): 405-407, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34661160

RESUMO

As a general rule, successful antineoplastic treatments induce an antitumor immune response, even if they were initially designed to target cancer cell-autonomous pathways. In this issue of Blood Cancer Discovery, Gulla and colleagues reveal that the proteasome inhibitor bortezomib induces immunogenic stress and death in multiple myeloma cells, thus explaining its therapeutic efficacy. See related article by Gulla et al., p. 468.

11.
Oncoimmunology ; 10(1): 1973197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712511

RESUMO

Immunogenic cell death (ICD) has initially been discovered in the context of chemotherapy. High-dose crizotinib also stimulates ICD, as we described for non-small cell lung cancer lacking activating chromosomal aberrations of ALK or ROS1, the usual targets of crizotinib, indicating that crizotinib may act through off-target effects. However, we found that low-dose of ALK inhibitors, crizotinib and ceritinib, may stimulate ICD in anaplastic large cell lymphoma, in which ALK is activated due to a chromosomal translocation, suggesting on target ICD-promoting effects.

12.
Mol Cancer ; 20(1): 128, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34607583

RESUMO

Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.

14.
Aging (Albany NY) ; 13(17): 20860-20885, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34517343

RESUMO

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.


Assuntos
COVID-19/sangue , COVID-19/patologia , Neoplasias/sangue , Neoplasias/virologia , Poliaminas/sangue , Acetilação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/microbiologia , COVID-19/virologia , Estudos de Coortes , Citocinas/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Metaboloma , Pessoa de Meia-Idade , Propionatos/sangue , Índice de Gravidade de Doença , Adulto Jovem , ortoaminobenzoatos/sangue
15.
Cell Death Differ ; 28(10): 2843-2856, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34465893

RESUMO

Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.

16.
Oncoimmunology ; 10(1): 1968595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527429

RESUMO

It has been an open conundrum why primary sclerosing cholangitis (PSC) is a major risk factor for developing cholangiocarcinoma (CAA), while primary biliary cholangitis (PBC) is not. In mouse models of PSC and PBC, it turned out that the latter condition, an autoimmune disease affecting the bile ducts, reduces transgene-induced cholangiocarcinogenesis, as well as the progression of subcutaneously implanted CCA. This CCA-delaying effect is lost upon depletion of T lymphocytes and involves tumor infiltration by T cell clonotypes that are also found in PBC lesions. Hence, organ-specific autoimmunity may improve immunosurveillance.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Colangite Esclerosante , Cirrose Hepática Biliar , Animais , Autoimunidade , Neoplasias dos Ductos Biliares/etiologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Colangite Esclerosante/patologia , Cirrose Hepática Biliar/patologia , Camundongos
17.
Nat Rev Immunol ; 21(10): 615, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34580459
18.
Artigo em Inglês | MEDLINE | ID: mdl-34562639

RESUMO

BACKGROUND & AIMS: Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis. METHODS: In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4flox/flox mice). Acute or chronic pancreatitis was induced in these mice (Gpx4flox/flox mice served as controls) by cerulein injections or a Lieber-DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses. RESULTS: Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non-adenosine triphosphatase 4-dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice. CONCLUSIONS: Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.

19.
J Exp Med ; 218(10)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34495298

RESUMO

Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.

20.
STAR Protoc ; 2(3): 100732, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34430908

RESUMO

Here, we describe a protocol for CRISPR/Cas9-mediated gene knockout in conditionally immortalized immature dendritic cells (DCs), which can be limitlessly expanded before differentiation. This facilitates the genetic screening of DC functions in vitro including assessment of phagocytosis, cytokine production, expression of co-stimulatory or co-inhibitory molecules, and antigen presentation, as well as evaluation of the capacity to elicit anticancer immune responses in vivo. Altogether, these approaches described in this protocol allow investigators to link the genotype of DCs to their phenotype. For complete details on the use and execution of this protocol, please refer to Le Naour et al. (2020).

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