Summary
The immunogenicity of cancer cells is an emerging determinant of anti‐cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell‐based vaccines, immune‐checkpoint ...blockers, and adoptive T‐cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti‐cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death (ICD), which is hallmarked by the emission of damage‐associated molecular patterns (DAMPs); molecules analogous to pathogen‐associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD‐associated danger signals favor immunomodulatory responses that lead to tumor‐associated antigens (TAAs)‐directed T‐cell immunity, which paves way for the removal of residual, treatment‐resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate “altered‐self mimicry” i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/IFN responses or pathogen response‐like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non‐self and danger models, which have shaped the field of cell death immunology.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
It is now well established that cancer cells co-exist within a complex environment with stromal cells and depend for their growth and dissemination on tight and plastic interactions with components ...of the tumor microenvironment (TME). Cancer cells incite the formation of new blood and lymphatic vessels from preexisting vessels to cope with their high nutrient/oxygen demand and favor tumor outgrowth. Research over the past decades has highlighted the crucial role played by tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. The structurally and functionally aberrant tumor vasculature contributes to the protumorigenic and immunosuppressive TME by maintaining a cancer cell's permissive environment characterized by hypoxia, acidosis, and high interstitial pressure, while simultaneously generating a physical barrier to T cells' infiltration. Recent research moreover has shown that blood endothelial cells forming the tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Likewise, during tumorigenesis the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Beyond carcinogenesis, the erratic tumor vasculature has been recently implicated in mechanisms of therapy resistance, including those limiting the efficacy of clinically approved immunotherapies, such as immune checkpoint blockers and adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting the major role played by tumor-associated blood and lymphatic vasculature in thwarting immunosurveillance mechanisms and antitumor immunity. Moreover, we also discuss novel therapeutic approaches targeting the tumor vasculature and their potential to help overcoming immunotherapy resistance.
Disturbance in the folding capacity of the endoplasmic reticulum (ER), caused by a variety of endogenous and exogenous insults, prompts a cellular stress condition known as ER stress. ER stress is ...initially shaped to re-establish ER homeostasis through the activation of an integrated intracellular signal transduction pathway termed as unfolded protein response (UPR). However, when ER stress is too severe or prolonged, the pro-survival function of the UPR turns into a toxic signal, which is predominantly executed by mitochondrial apoptosis. Moreover, accumulating evidence implicates ER stress pathways in the activation of various ‘classical’ inflammatory processes in and around the tumour microenvironment. In fact, ER stress pathways evoked by certain conventional or experimental anticancer modalities have been found to promote anti-tumour immunity by enhancing immunogenicity of dying cancer cells. Thus, the ER functions as an essential sensing organelle capable of coordinating stress pathways crucially involved in maintaining the cross-talk between the cancer cell’s intracellular and extracellular environment. In this review we discuss the emerging link between ER stress, cell fate decisions and immunomodulation and the potential therapeutic benefit of targeting this multifaceted signaling pathway in anticancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Type I interferons (IFNs) facilitate cancer immunosurveillance, antitumor immunity and antitumor efficacy of conventional cell death-inducing therapies (chemotherapy/radiotherapy) as well as ...immunotherapy. Moreover, it is clear that dendritic cells (DCs) play a significant role in aiding type I IFN-driven immunity. Owing to these antitumor properties several immunotherapies involving, or inducing, type I IFNs have received considerable clinical attention, e.g., recombinant IFNα2 or agonists targeting pattern recognition receptor (PRR) pathways like Toll-like receptors (TLRs), cGAS-STING or RIG-I/MDA5/MAVS. A series of preclinical and clinical evidence concurs that the success of anticancer therapy hinges on responsiveness of both cancer cells and DCs to type I IFNs. In this article, we discuss this link between type I IFNs and DCs in the context of cancer biology, with particular attention to mechanisms behind type I IFN production, their impact on DC driven anticancer immunity, and the implications of this for cancer immunotherapy, including DC-based vaccines.
Type I interferons (IFNs) comprise of pro-inflammatory cytokines created, as well as sensed, by all nucleated cells with the main objective of blocking pathogens-driven infections. Owing to this ...broad range of influence, type I IFNs also exhibit critical functions in many sterile inflammatory diseases and immunopathologies, especially those associated with endoplasmic reticulum (ER) stress-driven signaling pathways. Indeed, over the years accumulating evidence has indicated that the presence of ER stress can influence the production, or sensing of, type I IFNs induced by perturbations like pattern recognition receptor (PRR) agonists, infections (bacterial, viral or parasitic) or autoimmunity. In this article we discuss the link between type I IFNs and ER stress in various diseased contexts. We describe how ER stress regulates type I IFNs production or sensing, or how type I IFNs may induce ER stress, in various circumstances like microbial infections, autoimmunity, diabetes, cancer and other ER stress-related contexts.
Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death ...(ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tumours are a form of pseudo-organs with their own microenvironment where the cancer cells nurture a dysfunctional immune environment incapable of inciting anti-tumour immunity. It had been proposed ...that the only way to counteract such an immune system dysfunction in tumours is by eliciting, therapeutically, a cancer cell death pathway that is accompanied by high immunogenicity and possibly inhibits or reduces the influence of the pro-tumourigenic cytokine signalling. Subsequently, a small and a large-scale screening study as well as several targeted studies found that few, selected anticancer therapeutic regimens are able to induce a promising kind of cancer cell demise called immunogenic cell death (ICD), which can activate the immune system owing to the spatiotemporally defined emission of danger signals. Recently, photodynamic therapy (PDT) utilizing the photosensitiser, hypericin (Hyp), became the first PDT paradigm characterized to be capable of inducing bona fide ICD. In the present perspective, we discuss the various technical, conceptual, and molecular advancements and unprecedented results revealed by Hyp-PDT that have influenced the fields of ICD, ER stress biology, cancer cell death, anti-cancer immune responses, photoimmunology and PDT.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Understanding the genetic basis of immunological processes and their overall dynamics under the influence of population immunogenetics and host-microbe interactions has been at the core of health and ...disease research. Our understanding of these dynamics has recently undergone a paradigm shift with the application of high-resolution single cell or spatial omics technologies that have facilitated a deeper understanding of healthy or diseased immune milieu. At Genes & Immunity, we wish to revamp the journal to cater to these trends and bring together researchers working at these multidisciplinary interfaces of immunology and genetics, with the aim of advancing fundamental and translational knowledge while revealing new immunotherapy or biomarker modalities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Highlights • Autophagy is an intracellular recycling pathway with an emerging plastic role in cancer. • Autophagy modulates both cancer cell-autonomous and non-autonomous processes. • The interface ...between cancer and stromal cells autophagy models the tumor landscape. • Autophagy impacts immunosurveillance and antitumor immunity. • Understanding how autophagy modulators affect tumor stroma is key in cancer therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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