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Showing papers by "Guido Kroemer published in 2015"


Journal ArticleDOI
27 Nov 2015-Science
TL;DR: A key role is revealed for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade, which is found to depend on distinct Bacteroides species in mice and patients.
Abstract: Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

2,360 citations


Journal ArticleDOI
TL;DR: The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy.

1,094 citations


Journal ArticleDOI
TL;DR: The differential impact of autophagy on distinct phases of tumorigenesis is discussed and the implications of this concept for the use of Autophagy modulators in cancer therapy are discussed.
Abstract: Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

945 citations


Journal ArticleDOI
TL;DR: By influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression.

871 citations


Journal ArticleDOI
TL;DR: Accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance is discussed.
Abstract: Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells.

843 citations


Journal ArticleDOI
Lorenzo Galluzzi1, J M Bravo-San Pedro2, Ilio Vitale, Stuart A. Aaronson3, John M. Abrams4, Dieter Adam5, Emad S. Alnemri6, Lucia Altucci7, David W. Andrews8, Margherita Annicchiarico-Petruzzelli, Eric H. Baehrecke9, Nicolas G. Bazan10, Mathieu J.M. Bertrand11, Mathieu J.M. Bertrand12, Katiuscia Bianchi13, Katiuscia Bianchi14, Mikhail V. Blagosklonny15, Klas Blomgren16, Christoph Borner17, Dale E. Bredesen18, Dale E. Bredesen19, Catherine Brenner20, Catherine Brenner21, Michelangelo Campanella22, Eleonora Candi23, Francesco Cecconi23, Francis Ka-Ming Chan9, Navdeep S. Chandel24, Emily H. Cheng25, Jerry E. Chipuk3, John A. Cidlowski26, Aaron Ciechanover27, Ted M. Dawson28, Valina L. Dawson28, V De Laurenzi29, R De Maria, Klaus-Michael Debatin30, N. Di Daniele23, Vishva M. Dixit31, Brian David Dynlacht32, Wafik S. El-Deiry33, Gian Maria Fimia34, Richard A. Flavell35, Simone Fulda36, Carmen Garrido37, Marie-Lise Gougeon38, Douglas R. Green, Hinrich Gronemeyer39, György Hajnóczky6, J M Hardwick28, Michael O. Hengartner40, Hidenori Ichijo41, Bertrand Joseph16, Philipp J. Jost42, Thomas Kaufmann43, Oliver Kepp2, Daniel J. Klionsky44, Richard A. Knight45, Richard A. Knight22, Sharad Kumar46, Sharad Kumar47, John J. Lemasters48, Beth Levine49, Beth Levine50, Andreas Linkermann5, Stuart A. Lipton, Richard A. Lockshin51, Carlos López-Otín52, Enrico Lugli, Frank Madeo53, Walter Malorni54, Jean-Christophe Marine55, Seamus J. Martin56, J-C Martinou57, Jan Paul Medema58, Pascal Meier, Sonia Melino23, Noboru Mizushima41, Ute M. Moll59, Cristina Muñoz-Pinedo, Gabriel Núñez44, Andrew Oberst60, Theocharis Panaretakis16, Josef M. Penninger, Marcus E. Peter24, Mauro Piacentini23, Paolo Pinton61, Jochen H. M. Prehn62, Hamsa Puthalakath63, Gabriel A. Rabinovich64, Kodi S. Ravichandran65, Rosario Rizzuto66, Cecília M. P. Rodrigues67, David C. Rubinsztein68, Thomas Rudel69, Yufang Shi70, Hans-Uwe Simon43, Brent R. Stockwell71, Brent R. Stockwell49, Gyorgy Szabadkai66, Gyorgy Szabadkai22, Stephen W.G. Tait72, H. L. Tang28, Nektarios Tavernarakis73, Nektarios Tavernarakis74, Yoshihide Tsujimoto, T Vanden Berghe12, T Vanden Berghe11, Peter Vandenabeele11, Peter Vandenabeele12, Andreas Villunger75, Erwin F. Wagner76, Henning Walczak22, Eileen White77, W. G. Wood78, Junying Yuan79, Zahra Zakeri80, Boris Zhivotovsky16, Boris Zhivotovsky81, Gerry Melino23, Gerry Melino45, Guido Kroemer1 
Paris Descartes University1, Institut Gustave Roussy2, Mount Sinai Hospital3, University of Texas Southwestern Medical Center4, University of Kiel5, Thomas Jefferson University6, Seconda Università degli Studi di Napoli7, University of Toronto8, University of Massachusetts Medical School9, Louisiana State University10, Flanders Institute for Biotechnology11, Ghent University12, Cancer Research UK13, Queen Mary University of London14, Roswell Park Cancer Institute15, Karolinska Institutet16, University of Freiburg17, Buck Institute for Research on Aging18, University of California, San Francisco19, Université Paris-Saclay20, French Institute of Health and Medical Research21, University College London22, University of Rome Tor Vergata23, Northwestern University24, Memorial Sloan Kettering Cancer Center25, National Institutes of Health26, Technion – Israel Institute of Technology27, Johns Hopkins University28, University of Chieti-Pescara29, University of Ulm30, Genentech31, New York University32, Pennsylvania State University33, University of Salento34, Yale University35, Goethe University Frankfurt36, University of Burgundy37, Pasteur Institute38, University of Strasbourg39, University of Zurich40, University of Tokyo41, Technische Universität München42, University of Bern43, University of Michigan44, Medical Research Council45, University of South Australia46, University of Adelaide47, Medical University of South Carolina48, Howard Hughes Medical Institute49, University of Texas at Dallas50, St. John's University51, University of Oviedo52, University of Graz53, Istituto Superiore di Sanità54, Katholieke Universiteit Leuven55, Trinity College, Dublin56, University of Geneva57, University of Amsterdam58, Stony Brook University59, University of Washington60, University of Ferrara61, Royal College of Surgeons in Ireland62, La Trobe University63, University of Buenos Aires64, University of Virginia65, University of Padua66, University of Lisbon67, University of Cambridge68, University of Würzburg69, Soochow University (Suzhou)70, Columbia University71, University of Glasgow72, University of Crete73, Foundation for Research & Technology – Hellas74, Innsbruck Medical University75, Carlos III Health Institute76, Rutgers University77, University of Minnesota78, Harvard University79, City University of New York80, Moscow State University81
TL;DR: The Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Abstract: Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

809 citations


Journal ArticleDOI
TL;DR: Experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy are reviewed.
Abstract: Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.

358 citations


Journal ArticleDOI
TL;DR: The gut microbiota and its interactions with the host immune system play a role in oncogenesis and can alter the effectiveness of anticancer agents.
Abstract: Changes in the interactions among the gut microbiota, intestinal epithelium, and host immune system are associated with many diseases, including cancer. We discuss how environmental factors infuence this cross-talk during oncogenesis and tumor progression and how manipulations of the gut microbiota might improve the clinical activity of anticancer agents.

357 citations


Journal ArticleDOI
20 Nov 2015-Science
TL;DR: A loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) was identified that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy.
Abstract: Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.

342 citations


Journal ArticleDOI
19 Mar 2015-Oncogene
TL;DR: Recent findings suggest that another of its core components is represented by the c subunit of mitochondrial ATP synthase, the supramolecular entity that is believed to mediate MPT.
Abstract: The term mitochondrial permeability transition (MPT) is commonly used to indicate an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Widespread MPT has catastrophic consequences for the cell, de facto marking the boundary between cellular life and death. MPT results indeed in the structural and functional collapse of mitochondria, an event that commits cells to suicide via regulated necrosis or apoptosis. MPT has a central role in the etiology of both acute and chronic diseases characterized by the loss of post-mitotic cells. Moreover, cancer cells are often relatively insensitive to the induction of MPT, underlying their increased resistance to potentially lethal cues. Thus, intense efforts have been dedicated not only at the understanding of MPT in mechanistic terms, but also at the development of pharmacological MPT modulators. In this setting, multiple mitochondrial and extramitochondrial proteins have been suspected to critically regulate the MPT. So far, however, only peptidylprolyl isomerase F (best known as cyclophilin D) appears to constitute a key component of the so-called permeability transition pore complex (PTPC), the supramolecular entity that is believed to mediate MPT. Here, after reviewing the structural and functional features of the PTPC, we summarize recent findings suggesting that another of its core components is represented by the c subunit of mitochondrial ATP synthase.

308 citations


Journal ArticleDOI
TL;DR: This work discusses current combinatorial approaches to convert otherwise non-immunogenic instances of RCD into bona fide ICD, and suggests that novel therapeutic regimens that trigger ICD are urgently awaited.
Abstract: The term “immunogenic cell death” (ICD) is commonly employed to indicate a peculiar instance of regulated cell death (RCD) that engages the adaptive arm of the immune system. The inoculation of cancer cells undergoing ICD into immunocompetent animals elicits a specific immune response associated with the establishment of immunological memory. Only a few agents are intrinsically endowed with the ability to trigger ICD. These include a few chemotherapeutics that are routinely employed in the clinic, like doxorubicin, mitoxantrone, oxaliplatin, and cyclophosphamide, as well as some agents that have not yet been approved for use in humans. Accumulating clinical data indicate that the activation of adaptive immune responses against dying cancer cells is associated with improved disease outcome in patients affected by various neoplasms. Thus, novel therapeutic regimens that trigger ICD are urgently awaited. Here, we discuss current combinatorial approaches to convert otherwise non-immunogenic instances of RCD into bona fide ICD.

Journal ArticleDOI
TL;DR: The main molecular, immunological, preclinical, and clinical aspects of ICD are summarized and tabulate in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.
Abstract: The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Journal ArticleDOI
TL;DR: Several major disease categories are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification, and driven by promising preclinical results, several clinical trials are exploring autophileagy as a therapeutic target.
Abstract: Autophagy ("self-eating") constitutes one of the most spectacular yet subtly regulated phenomena in cell biology. Similarly to cell division, differentiation, and death, autophagy is perturbed in multiple diseases, in that excessive or deficient autophagy may contribute to pathogenesis. Numerous attempts have been launched to identify specific inducers or inhibitors of autophagy and to use them for the therapeutic correction of its deregulation. At present, several major disease categories (including but not limited to age-related, cardiovascular, infectious, neoplastic, neurodegenerative, and metabolic pathologies) are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification. Driven by promising preclinical results, several clinical trials are exploring autophagy as a therapeutic target.

Journal ArticleDOI
TL;DR: It is pointed out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.
Abstract: The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.

Journal ArticleDOI
11 Sep 2015-Science
TL;DR: CGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses, and it was shown that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP.
Abstract: Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2′3′-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.

Journal ArticleDOI
TL;DR: Results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent Autophagy inducers including spermidine de facto act as EP300 inhibitors.
Abstract: Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.

Journal ArticleDOI
TL;DR: Recent developments on anticancer chemotherapy based on ICD inducers are discussed, including the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid.
Abstract: The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.

Journal ArticleDOI
TL;DR: The molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophile products or functions are summarized.

Journal ArticleDOI
TL;DR: It is shown that the abundance of phosphatidylethanolamine positively regulates autophagy and that organismal life or healthspan could be positively influenced by the consumption of ethanolamine-rich food.
Abstract: Autophagy is a cellular recycling program that retards ageing by efficiently eliminating damaged and potentially harmful organelles and intracellular protein aggregates. Here, we show that the abundance of phosphatidylethanolamine (PE) positively regulates autophagy. Reduction of intracellular PE levels by knocking out either of the two yeast phosphatidylserine decarboxylases (PSD) accelerated chronological ageing-associated production of reactive oxygen species and death. Conversely, the artificial increase of intracellular PE levels, by provision of its precursor ethanolamine or by overexpression of the PE-generating enzyme Psd1, significantly increased autophagic flux, both in yeast and in mammalian cell culture. Importantly administration of ethanolamine was sufficient to extend the lifespan of yeast (Saccharomyces cerevisiae), mammalian cells (U2OS, H4) and flies (Drosophila melanogaster). We thus postulate that the availability of PE may constitute a bottleneck for functional autophagy and that organismal life or healthspan could be positively influenced by the consumption of ethanolamine-rich food.

Journal ArticleDOI
TL;DR: This work has identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery that contributes to the biogenesis of respiratory chain complexes and establishes an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.

Journal ArticleDOI
TL;DR: Unsaturated fatty acids induce a non‐canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus, and downregulation of BECN1 and PIK3C3 abolished palmitate‐ induced, but not oleate‐induced, Autophagy in human cancer cells.
Abstract: To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus. Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1(+/-) mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate. Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus.

Journal ArticleDOI
TL;DR: This study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.
Abstract: The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4+ T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

Journal ArticleDOI
TL;DR: Clinical data indicating that DAMPs and DAMP-associated stress responses might have prognostic or predictive value for cancer patients are reviewed.
Abstract: It is now clear that human neoplasms form, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system. In particular, accumulating evidence demonstrates that the efficacy of most, if not all, chemo- and radiotherapeutic agents commonly employed in the clinic critically depends on the (re)activation of tumor-targeting immune responses. One of the mechanisms whereby conventional chemotherapeutics, targeted anticancer agents, and radiotherapy can provoke a therapeutically relevant, adaptive immune response against malignant cells is commonly known as “immunogenic cell death.” Importantly, dying cancer cells are perceived as immunogenic only when they emit a set of immunostimulatory signals upon the activation of intracellular stress response pathways. The emission of these signals, which are generally referred to as “damage-associated molecular patterns” (DAMPs), may therefore predict whether patients will respond to chemotherapy or not, at least in some settings. Here, we review clinical data indicating that DAMPs and DAMP-associated stress responses might have prognostic or predictive value for cancer patients.

Journal ArticleDOI
TL;DR: The authors found that the key lies in the predominant isoform of a receptor that natural killer cells use to interact with neuroblastoma cells and that the balance between isoforms of this receptor on a patient’s cells can help predict survival.
Abstract: The immunosurveillance mechanisms governing high-risk neuroblastoma (HR-NB), a major pediatric malignancy, have been elusive. We identify a potential role for natural killer (NK) cells, in particular the interaction between the NK receptor NKp30 and its ligand, B7-H6, in the metastatic progression and survival of HR-NB after myeloablative multimodal chemotherapy and stem cell transplantation. NB cells expressing the NKp30 ligand B7-H6 stimulated NK cells in an NKp30-dependent manner. Serum concentration of soluble B7-H6 correlated with the down-regulation of NKp30, bone marrow metastases, and chemoresistance, and soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. The expression of distinct NKp30 isoforms affecting the polarization of NK cell functions correlated with 10-year event-free survival in three independent cohorts of HR-NB in remission from metastases after induction chemotherapy (n = 196, P 18 months. We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of NB patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification.


Journal ArticleDOI
TL;DR: The latest advances in the development of peptide vaccines for cancer therapy are summarized, with a focus on the identification of so-called tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication.
Abstract: Malignant cells express antigens that can be harnessed to elicit anticancer immune responses. One approach to achieve such goal consists in the administration of tumor-associated antigens (TAAs) or peptides thereof as recombinant proteins in the presence of adequate adjuvants. Throughout the past decade, peptide vaccines have been shown to mediate antineoplastic effects in various murine tumor models, especially when administered in the context of potent immunostimulatory regimens. In spite of multiple limitations, first of all the fact that anticancer vaccines are often employed as therapeutic (rather than prophylactic) agents, this immunotherapeutic paradigm has been intensively investigated in clinical scenarios, with promising results. Currently, both experimentalists and clinicians are focusing their efforts on the identification of so-called tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication, as well as to combinatorial immunostimulatory interventi...

Journal ArticleDOI
TL;DR: The role of the ER stress response in ICD and the potential value of eIF2α phosphorylation as a biomarker for this clinically relevant variant of apoptosis are discussed.

Journal ArticleDOI
TL;DR: Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1+ LC3B+ double-positive tumors had a better prognosis than BC that lacked one or both of these markers.
Abstract: In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.

Journal ArticleDOI
TL;DR: The BH3 mimetic ABT-737 induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells.
Abstract: Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT-737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.

Journal ArticleDOI
TL;DR: The results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.
Abstract: STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3(-/-) cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell-dependent and T lymphocyte-mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3(-/-) cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3(Y705F)) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3(-/-) cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3(-/-) and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells.