Nejvíce citovaný článek - PubMed ID 25941621
Consensus guidelines for the detection of immunogenic cell death
The emerged field of non-thermal plasma (NTP) shows great potential in the alteration of cell redox status, which can be utilized as a promising therapeutic implication. In recent years, the NTP field considerably progresses in the modulation of immune cell function leading to promising in vivo results. In fact, understanding the underlying cellular mechanisms triggered by NTP remains incomplete. In order to boost the field closer to real-life clinical applications, there is a need for a critical overview of the current state-of-the-art. In this review, we conduct a critical analysis of the NTP-triggered modulation of immune cells. Importantly, we analyze pitfalls in the field and identify persisting challenges. We show that the identification of misconceptions opens a door to the development of a research strategy to overcome these limitations. Finally, we propose the idea that solving problems highlighted in this review will accelerate the clinical translation of NTP-based treatments.
- Klíčová slova
- cell signaling, cytotoxicity, immunomodulation, non-thermal plasma,
- MeSH
- buněčná imunita účinky léků MeSH
- lidé MeSH
- plazmové plyny farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- plazmové plyny MeSH
Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
- Klíčová slova
- immunology, molecular biology, oncology,
- MeSH
- imunogenní buněčná smrt genetika MeSH
- konsensus MeSH
- lidé MeSH
- molekulární biologie metody MeSH
- směrnice jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
The term 'immunogenic cell death' (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the preclinical and clinical development of ICD-eliciting chemotherapy as partner for immunotherapy, with a focus on trials assessing efficacy in the context of immunomonitoring.
- Klíčová slova
- Antigen-presenting cell, CAR T cells, autophagy, chemokines, cytokines, cytotoxic T lymphocyte, dendritic cell, endoplasmic reticulum stress, immune checkpoint blocker, type I interferon,
- MeSH
- adaptivní imunita MeSH
- imunogenní buněčná smrt MeSH
- imunoterapie MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- protinádorové látky * terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- protinádorové látky * MeSH
Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor-specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy.
- Klíčová slova
- CAVATAK, DNX-2401, HF10, MV-NIS, Maraba MG1, Pexa-Vec, REOLYSIN, T-VEC,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
High hydrostatic pressure (HHP) promotes key characteristics of immunogenic cell death (ICD), in thus far resembling immunogenic chemotherapy and ionizing irradiation. Here, we demonstrate that cancer cells succumbing to HHP induce CD4+ and CD8+ T cell-dependent protective immunity in vivo. Moreover, we show that cell death induction by HHP relies on the overproduction of reactive oxygen species (ROS), causing rapid establishment of the integrated stress response, eIF2α phosphorylation by PERK, and sequential caspase-2, -8 and -3 activation. Non-phosphorylatable eIF2α, depletion of PERK, caspase-2 or -8 compromised calreticulin exposure by cancer cells succumbing to HHP but could not inhibit death. Interestingly, the phagocytosis of HHP-treated malignant cells by dendritic cells was suppressed by the knockdown of caspase-2 in the former. Thus, caspase-2 mediates a key function in the interaction between dying cancer cells and antigen presenting cells. Our results indicate that the ROS→PERK→eIF2α→caspase-2 signaling pathway is central for the perception of HHP-driven cell death as immunogenic.
- Klíčová slova
- Caspases, ER stress, ecto-CALR, high hydrostatic pressure, immunogenic cell death,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called "damage-associated molecular patterns," DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.
- MeSH
- akutní myeloidní leukemie farmakoterapie genetika imunologie metabolismus MeSH
- alarminy metabolismus MeSH
- blastická krize imunologie patologie MeSH
- buněčná smrt MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- fenotyp MeSH
- genetická transkripce MeSH
- imunita MeSH
- kalretikulin metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- multivariační analýza MeSH
- proporcionální rizikové modely MeSH
- proteiny tepelného šoku HSP70 metabolismus MeSH
- proteiny tepelného šoku HSP90 metabolismus MeSH
- regulace genové exprese u leukemie MeSH
- stanovení celkové genové exprese MeSH
- Th1 buňky imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alarminy MeSH
- CALR protein, human MeSH Prohlížeč
- kalretikulin MeSH
- proteiny tepelného šoku HSP70 MeSH
- proteiny tepelného šoku HSP90 MeSH
The demographics of squamous cell carcinoma of the head and neck (SCCHN) is marked by a growing number of patients aged 65 and over, which is in line with global projections for other cancer types. In developed countries, more than half of new SCCHN cases are diagnosed in older people, and in 15 years from now, the proportion is expected to rise by more than 10%. Still, a high-level evidence-based consensus to guide the clinical decision process is strikingly lacking. The available data from retrospective studies and subset analyses of prospective trials suffer from a considerable underrepresentation of senior participants. The situation is even more challenging in the recurrent and/or metastatic setting, where usually only palliative measures are employed. Nevertheless, it is becoming clear that, if treated irrespective of chronological age, fit elderly patients in a good general condition and with a low burden of comorbidities may derive a similar survival advantage as their younger counterparts. Despite that, undertreatment represents a widespread phenomenon and, together with competing non-cancer mortality, is suggested to be an important cause of the worse treatment outcomes observed in this population. Due to physiological changes in drug metabolism occurring with advancing age, the major concerns relate to chemotherapy administration. In locally advanced SCCHN, concurrent chemoradiotherapy in patients over 70 years remains a point of controversy owing to its possibly higher toxicity and questionable benefit. However, accumulating evidence suggests that it should, indeed, be considered in selected cases when biological age is taken into account. Results from a randomized trial conducted in lung cancer showed that treatment selection based on a comprehensive geriatric assessment (CGA) significantly reduced toxicity. However, a CGA is time-consuming and not necessary for all patients. To overcome this hurdle, geriatric screening tools have been introduced to decide who needs such a full evaluation. Among the various screening instruments, G8 and Flemish version of the Triage Risk Screening Tool were prospectively verified and found to have prognostic value. We, therefore, conclude that also in SCCHN, the application of elderly specific prospective trials and integration of clinical practice-oriented assessment tools and predictive models should be promoted.
- Klíčová slova
- chemotherapy, comprehensive geriatric assessment, head and neck cancer, immunotherapy, radiotherapy, screening tools, surgery, targeted therapy,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation.
Progressing malignancies establish robust immunosuppressive networks that operate both systemically and locally. In particular, as tumors escape immunosurveillance, they recruit increasing amounts of myeloid and lymphoid cells that exert pronounced immunosuppressive effects. These cells not only prevent the natural recognition of growing neoplasms by the immune system, but also inhibit anticancer immune responses elicited by chemo-, radio- and immuno therapeutic interventions. Throughout the past decade, multiple strategies have been devised to counteract the accumulation or activation of tumor-infiltrating immunosuppressive cells for therapeutic purposes. Here, we review recent preclinical and clinical advances on the use of small molecules that target the immunological tumor microenvironment for cancer therapy. These agents include inhibitors of indoleamine 2,3-dioxigenase 1 (IDO1), prostaglandin E2, and specific cytokine receptors, as well as modulators of intratumoral purinergic signaling and arginine metabolism.
- Klíčová slova
- Adenosine, IDO1, PGE2, Tregs, myeloid-derived suppressor cells, tumor-associated macrophages,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.
- Klíčová slova
- Ampligen™, G100, Hiltonol™, bacillus Calmette-Guérin, imiquimod, motolimod,
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
