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Mammalian cells responding to specific perturbations of homeostasis can undergo a regulated variant of cell death that elicits adaptive immune responses. As immunogenic cell death (ICD) can only occur in a precise cellular and organismal context, it should be conceptually differentiated from instances of immunostimulation or inflammatory responses that do not mechanistically depend on cellular demise. Here, we critically discuss key conceptual and mechanistic aspects of ICD and its implications for cancer (immuno)therapy. [ABSTRACT FROM AUTHOR]

When cellular damage can be efficiently repaired and/or microenvironmental perturbations are limited in intensity and duration, cells can recover physiological functions in the context of re-established homeostasis [[2]]. These mechanisms encompass, but are not limited to: the DNA damage response [[4]], the unfolded protein response [[5]], and autophagy [[6]]. On the contrary, when damage is beyond repair and/or stressful stimuli are excessively intense or prolonged, the same pathways that initially attempt to restore physiological homeostasis instead engage signaling modules that actively promote cellular demise, a process that has been dubbed regulated cell death (RCD) [[1]]. Eukaryotic cells exposed to extreme perturbations of homeostasis, which are relatively rare in nature, succumb to the unregulated and virtually immediate physical breakdown of their components, a process that has been dubbed accidental cell death (ACD) [[1]]. [Extracted from the article]

Newly formed malignant cells must escape immunosurveillance to generate progressing neoplastic lesions of clinical relevance. Recent data indicate that the immunogenicity of nascent cancer cells, at least in some settings, is dictated by inherent epigenetic mechanisms rather than by immunoediting and the consequent Darwinian selection of poorly immunogenic phenotypes. [ABSTRACT FROM AUTHOR]

Mitochondrial outer membrane permeabilization (MOMP) is crucial for the cytosolic accumulation of mitochondrial DNA (mtDNA) species that are required to jumpstart innate and adaptive immunity. Recent data reported by Ghosh et al. suggest that tumor protein p53 regulates MOMP-dependent type I interferon (IFN) production, not only via MOMP-promoting effects, but also by directing mtDNA-degrading exonucleases to proteasomal processing. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress can stimulate calreticulin (CALR) presentation on the cell surface, promoting the phagocytic uptake of stressed cells by myeloid cells. Recent findings from Wattrus et al. demonstrate that zebrafish and mouse embryonic macrophages engulf CALR-exposing nascent hematopoietic stem cells to ensure the selective survival of stem cells apt for adult hematopoiesis. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors mediate poorly overlapping cytostatic and immunostimulatory effects, suggesting that combinatorial regimens may enable supra- additive tumor control. Our preclinical findings demonstrate that administration schedule stands out as a major determinant of efficacy when RT and CDK4/6 inhibitors are combined for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN) release by irradiated cancer cells is paramount for radiation therapy to elicit anticancer immunity. Our findings demonstrate that mitochondrial outer membrane permeabilization (MOMP) triggered by RT enables exposure of mitochondrial DNA to the cytosol, hence setting off CGAS-driven type I IFN synthesis. These data point to the existence of a therapeutically actionable mitochondrial checkpoint that restricts innate immune signaling in irradiated cancer cells. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid L-tryptophan (Trp) into the immunosuppressive metabolite L-kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications. [ABSTRACT FROM AUTHOR]

Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders. cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, in situ vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor [ABSTRACT FROM AUTHOR]

Carbohydrate-rich diets have been consistently associated with detrimental effects for human health, including diabetes and obesity. Moreover, high glucose levels appear to mediate immunosuppressive effects in preclinical tumor models. Recent data from Ferrere and colleagues point to the intriguing possibility that carbotoxicity may originate from the abolition of ketosis. [ABSTRACT FROM AUTHOR]

Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy. Highlights Canonical WNT signaling plays a central role in embryogenesis, tissue homeostasis, and wound repair. Deregulated WNT signaling is involved in virtually all stages of oncogenesis. Impaired anticancer immunity as a result of aberrant WNT signaling is emerging as a key contributor to tumor progression and resistance to treatment. Activation of canonical WNT signaling hampers T cell-mediated anticancer immune responses by multiple mechanisms including immune exclusion. [ABSTRACT FROM AUTHOR]

Unscheduled tetraploidy is a metastable state that rapidly evolves into aneuploidy. Recent findings reported by Gemble et al. demonstrate that freshly formed tetraploid cells fail to accumulate the required amounts of DNA replication factors during the first G 1 phase after whole-genome duplication (WGD), culminating in genetic instability in the subsequent S phase and extensive karyotypic alterations. [ABSTRACT FROM AUTHOR]

Although somatic KRAS mutations are common in human tumors, no inhibitor of mutant KRAS was clinically available until recently. Canon and colleagues describe the ability of a clinically available KRASG12C inhibitor to drive immunogenic cancer cell death, thus constituting a promising combinatorial partner for immune checkpoint blockers. [ABSTRACT FROM AUTHOR]

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research. [ABSTRACT FROM AUTHOR]

Several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting the existence of a “metabolic clock” that controls aging. Multiple inborn defects in metabolic circuitries accelerate aging, whereas genetic loci linked to exceptional longevity influence metabolism. Each of the nine hallmarks of aging is connected to undesirable metabolic alterations. The main features of the “westernized” lifestyle, including hypercaloric nutrition and sedentariness, can accelerate aging as they have detrimental metabolic consequences. Conversely, lifespan-extending maneuvers including caloric restriction impose beneficial pleiotropic effects on metabolism. The introduction of strategies that promote metabolic fitness may extend healthspan in humans. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are widely used for the management of disease- or therapy-related complications in cancer patients. Recent data indicate that activation of GC receptors (GRs) precipitates breast cancer progression by favoring metastatic dissemination and cell survival at distant sites. These findings call for the re-evaluation of GC usage in patients with cancer. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a recent Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. [ABSTRACT FROM AUTHOR]

Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis. [ABSTRACT FROM AUTHOR]

Some forms of regulated cell death, such as apoptosis, are precipitated by the activation of cysteine proteases of the caspase family, including caspase 8, 9, and 3. Other caspases, such as caspase 1 and 4, are well known for their pro-inflammatory functions but regulate cell death in a limited number of pathophysiological settings. Accumulating evidence suggests that the most conserved function of mammalian caspases is not to control cell death sensu stricto, but to regulate inflammatory and immune reactions to dying cells and infectious challenges. Here, we review the molecular and cellular mechanisms though which mammalian caspases connect cell-death signaling to the maintenance of organismal homeostasis. [ABSTRACT FROM AUTHOR]

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological “side” effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. [ABSTRACT FROM AUTHOR]

Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates (“offer”) and the cellular need of autophagic products or functions for adaptation (“demand”). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize 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 autophagic products or functions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Large BAX/BAK pores that form during apoptosis enable mitochondrial nucleoids to access the cytosol, potentially leading to inflammatory signaling via CGAS. Under physiological conditions, however, BAX/BAK-dependent caspase activation rapidly dismantles dying cells to prevent inflammatory responses. BAX and BAK operate at the interface between apoptotic signaling and innate immunity control. [ABSTRACT FROM AUTHOR]

Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions. [ABSTRACT FROM AUTHOR]

Demaria and colleagues have recently identified three prime repair exonuclease 1 (TREX1) as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. TREX1 stands out as a promising target for the development of novel strategies to boost anticancer immune responses driven by radiation therapy (RT). [ABSTRACT FROM AUTHOR]

Two resource articles recently published in Cell demonstrate that the elevated phenotypic complexity of the immune infiltrate in human lung adenocarcinomas and renal cell carcinomas can be reliably dissected with mass cytometry. These findings may pave the way to a new era of precision cancer immunotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved mechanism of adaptation to adverse microenvironmental conditions, including limited nutrient supplies. Several sensors interacting with the autophagic machinery have evolved to detect fluctuations in key metabolic parameters. The signal transduction cascades operating downstream of these sensors are highly interconnected to control a spatially and chronologically coordinated autophagic response that maintains the health and function of individual cells while preserving organismal homeostasis. Here, we discuss the physiological regulation of autophagy by metabolic circuitries, as well as alterations of such control in disease. [ABSTRACT FROM AUTHOR]

It is now clear that apoptosis does not constitute the sole genetically encoded form of cell death. Rather, cells can spontaneously undertake or exogenously be driven into a cell death subroutine that manifests with necrotic features, yet can be inhibited by pharmacological and genetic interventions. As regulated necrosis (RN) plays a major role in both physiological scenarios ( e.g. , embryonic development) and pathological settings ( e.g. , ischemic disorders), consistent efforts have been made throughout the last decade toward the characterization of the molecular mechanisms that underlie this cell death modality. Contrarily to initial beliefs, RN does not invariably result from the activation of a receptor interacting protein kinase 3 (RIPK3)-dependent signaling pathway, but may be ignited by distinct molecular networks. Nowadays, various types of RN have been characterized, including (but not limited to) necroptosis, mitochondrial permeability transition (MPT)-dependent RN and parthanatos. Of note, the inhibition of only one of these modules generally exerts limited cytoprotective effects in vivo , underscoring the degree of interconnectivity that characterizes RN. Here, we review the signaling pathways, pathophysiological relevance and therapeutic implications of the major molecular cascades that underlie RN. [ABSTRACT FROM AUTHOR]

In a majority of pathophysiological settings, cell death is not accidental - it is controlled by a complex molecular apparatus. Such a system operates like a computer: it receives several inputs that inform on the current state of the cell and the extracellular microenvironment, integrates them and generates an output. Thus, depending on a network of signals generated at specific subcellular sites, cells can respond to stress by attemptinwg to recover homeostasis or by activating molecular cascades that lead to cell death by apoptosis or necrosis. Here, we discuss the mechanisms whereby cellular compartments - including the nucleus, mitochondria, plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosomes, cytoskeleton and cytosol - sense homeostatic perturbations and translate them into a cell-death-initiating signal. [ABSTRACT FROM AUTHOR]

Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel. [ABSTRACT FROM AUTHOR]

Highlights: [•] Uncontrolled inflammation exacerbates tissue damage in several pathological settings. [•] Chronic inflammatory conditions promote multiple human diseases including cancer. [•] The immune system also eliminates damaged – and hence potentially dangerous – cells. [•] Immunosurveillance plays a major role in the maintenance of tissue homeostasis. [Copyright &y& Elsevier]

Summary: Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including – but not limited to – cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. [ABSTRACT FROM AUTHOR]

Autophagy constitutes a mechanism for the sequestration and lysosomal degradation of various cytoplasmic structures, including damaged organelles and invading microorganisms. Autophagy not only represents an essential cell-intrinsic mechanism to protect against internal and external stress conditions but also shapes cellular immunity. Recent evidence indicates that autophagic responses in antigen-donor cells affect the release of several cytokines and “danger signals.” Thus, especially when it precedes cell death, autophagy alerts innate immune effectors to elicit cognate immune responses. Autophagy is also important for the differentiation, survival, and activation of myeloid and lymphoid cells. Accordingly, inherited mutations in autophagy-relevant genes are associated with immune diseases, whereas oncogenesis-associated autophagic defects promote the escape of developing tumors from immunosurveillance. Here, we discuss the regulation of autophagy in the course of cellular immune responses and emphasize its impact on the immunogenicity of antigen-donor cells and on the activity of antigen-presenting cells and T lymphocytes. [ABSTRACT FROM AUTHOR]

Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents. [Copyright &y& Elsevier]

Tetraploid cells-cells that contain twice the normal amount of DNA-are more prone to neoplastic transformation than their normal, diploid counterparts since they are genomically unstable and frequently undergo asymmetric, multipolar cell divisions. Similar to many other genomic aberrations, tetraploidization is normally avoided by multiple, nonredundant cell-intrinsic mechanisms that are tied to cell cycle checkpoints. Unexpectedly, tetraploidization is also under the control of a cell-extrinsic mechanism determined by the immune system. Indeed, oncogene- or carcinogen-induced cancers developing in immunodeficient mice contain cells with a higher DNA content than similar tumors growing in immunocompetent hosts. Moreover, cancer cell lines that have been rendered tetraploid in vitro grow normally in immunodeficient mice, yet almost fail to generate tumors in immunocompetent animals. One of the mechanisms whereby the immune system recognizes tetraploid cells originates from tetraploidy causing an endoplasmic reticulum (ER) stress response that culminates in the exposure of the ER protein calreticulin on the cell surface. Hence, tetraploidy exemplifies a potentially oncogenic alteration that is repressed by a combination of cell-autonomous mechanisms and immunosurveillance. Oncogenesis and tumor progression require the simultaneous failure of both such control systems. [ABSTRACT FROM AUTHOR]

Depending on the initiating stimulus, cancer cell death can be immuno-genic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the im-mune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing die emis-sion of immunogenic signals during ICD), or defects in immune effec-tors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subver-sion by pathogens also play major roles in antiviral immune responses. [ABSTRACT FROM AUTHOR]

Throughout more than 1.5 billion years of obligate endosymbiotic co-evolution, mitochondria have developed not only the capacity to control distinct molecular cascades leading to cell death but also the ability to sense (and react to) multiple situations of cellular stress, including viral infection. In addition, mitochondria can emit danger signals that alert the cell or the whole organism of perturbations in homeostasis, hence promoting the induction of cell-intrinsic or systemic adaptive responses, respectively. As such, mitochondria can be considered as master regulators of danger signalling. [ABSTRACT FROM AUTHOR]

During the last two decades, a number of approaches for the activation of the immune system against cancer has been developed. These include highly specific interventions, such as monoclonal antibodies, vaccines and cell-based therapies, as well as relatively unselective strategies, such as the systemic administration of adjuvants and immunomodulatory cytokines. Cytokines constitute a huge group of proteins that, taken together, regulate not only virtually all the aspects of innate and cognate immunity, but also several other cellular and organismal functions. Cytokines operate via specific transmembrane receptors that are expressed on the plasma membrane of target cells and, depending on multiple variables, can engage autocrine, paracrine or endocrine signaling pathways. Perhaps, the most appropriate term for defining the cytokine network is "pleiotropic": cytokines are produced by—and operate on—multiple, often overlapping, cell types, triggering context-depend biological outcomes as diverse as cell proliferation, chemotaxis, differentiation, inflammation, elimination of pathogens and cell death. Moreover, cytokines often induce the release of additional cytokines, thereby engaging self-amplificatory or self-inhibitory signaling cascades. In this Trial Watch, we will summarize the biological properties of cytokines and discuss the progress of ongoing clinical studies evaluating their safety and efficacy as immunomodulatory agents against cancer. [ABSTRACT FROM AUTHOR]

During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and cell-based therapies. Among the latter, adoptive cell transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of adoptive cell transfer as an anticancer therapy. [ABSTRACT FROM AUTHOR]

The success of anticancer chemotherapy relies at least in part on the induction of an immune response against tumor cells. Thus, tumors growing on mice that lack the pattern recognition receptor TLR4 or the purinergic receptor P2RX7 fail to respond to chemotherapy with anthracyclins or oxaliplatin in conditions in which the same neoplasms growing on immunocompetent mice would do so. Similarly, the therapeutic efficacy (measured as progression-free survival) of adjuvant chemotherapy with anthracyclins is reduced in breast cancer patients bearing loss-of-function alleles of TLR4 or P2RX7. TLR4 loss-of-function alleles also have a negative impact on the therapeutic outcome of oxaliplatin in colorectal cancer patients. Here, we report that loss-of-function TLR4 and P2RX7 alleles do not affect overall survival in non-small cell lung cancer (NSCLC) patients, irrespective of the administration and type of chemotherapy. The intrinsic characteristics of NSCLC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which near-to-always is based on cisplatin) may explain why two genes that affect the immune response to dying cells fail to influence the clinical progression of NSCLC patients. [ABSTRACT FROM AUTHOR]

It has recently become clear that the tumour microenvironment, and in particular the immune system, has a crucial role in modulating tumour progression and response to therapy. Indicators of an ongoing immune response, such as the composition of the intratumoural immune infiltrate, as well as polymorphisms in genes encoding immune modulators, have been correlated with therapeutic outcome. Moreover, several anticancer agents - including classical chemotherapeutics and targeted compounds - stimulate tumour-specific immune responses either by inducing the immunogenic death of tumour cells or by engaging immune effector mechanisms. Here, we discuss the molecular and cellular circuitries whereby cytotoxic agents can activate the immune system against cancer, and their therapeutic implications. [ABSTRACT FROM AUTHOR]

The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone. [ABSTRACT FROM AUTHOR]

Alterations of mitochondrial functions are linked to multiple degenerative or acute diseases. As mitochondria age in our cells, they become progressively inefficient and potentially toxic, and acute damage can trigger the permeabilization of mitochondria[ membranes to initiate apoptosis or necrosis. Moreover, mitochondria have an important role in pro-inflammatory signaling. Autophagic turnover of cellular constituents, be it general or specific for mitochondria (mitophagy), eliminates dysfunctional or damaged mitochondria, thus counteracting degeneration, dampening inflammation, and preventing unwarranted cell loss. Decreased expression of genes that regulate autophagy or mitophagy can cause degenerative diseases in which deficient quality control results in inflammation and the death of cell populations. Thus, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies. [ABSTRACT FROM AUTHOR]