Immunological tolerance of myeloma cells represents a critical obstacle in achieving long-term disease-free survival for multiple myeloma (MM) patients. Over the past two decades, remarkable preclinical efforts to understand MM biology have led to the clinical approval of several targeted and immunotherapeutic agents. Among them, it is now clear that chemotherapy can also make cancer cells "visible" to the immune system and thus reactivate anti-tumor immunity. This knowledge represents an important resource in the treatment paradigm of MM, whereas immune dysfunction constitutes a clear obstacle to the cure of the disease. In this review, we highlight the importance of defining the immunological effects of chemotherapy in MM with the goal of enhancing the clinical management of patients. This area of investigation will open new avenues of research to identify novel immunogenic anti-MM agents and inform the optimal integration of chemotherapy with immunotherapy.

• Klíčová slova
• DAMPs, ICD, immunogenic chemotherapy, microenvironment, myeloma,
• MeSH
• imunoterapie MeSH
• lidé MeSH
• mnohočetný myelom * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural 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
• antitumorózní látky * terapeutické užití   MeSH
• imunogenní buněčná smrt MeSH
• imunoterapie MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky * 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

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.

• Klíčová slova
• anti-tumor immunity, immunogenicity, immunotherapy, molecular medicine, oncoimmunology, patient prognosis, translational medicine,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• ATP, HMGB1, autophagy, calreticulin, endoplasmic reticulum stress, type I interferon,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• Klíčová slova
• ALL, acute lymphoblastic leukemia, AML, acute myeloid leukemia, CML, chronic myeloid leukemia, DAMP, damage-associated molecular pattern, EGFR, epidermal growth factor receptor, EOX, epirubicin plus oxaliplatin plus capecitabine, ER, endoplasmic reticulum, FDA, Food and Drug Administration, FOLFIRINOX, folinic acid plus 5-fluorouracil plus irinotecan plus oxaliplatin, FOLFOX, folinic acid plus 5-fluorouracil plus oxaliplatin, GEMOX, gemcitabine plus oxaliplatin, GM-CSF, granulocyte-macrophage colony-stimulating factor, HCC, hepatocellular carcinoma, ICD, immunogenic cell death, MM, multiple myeloma, NHL, non-Hodgkin's lymphoma, NSCLC, non-small cell lung carcinoma, TACE, transcatheter arterial chemoembolization, XELOX, capecitabine plus oxaliplatin, antigen-presenting cell, autophagy, damage-associated molecular pattern, dendritic cell, endoplasmic reticulum stress, mAb, monoclonal antibody, type I interferon,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

• MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory imunologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.

• Klíčová slova
• APC, antigen-presenting cell, ATF6, activating transcription factor 6, ATP release, BAK1, BCL2-antagonist/killer 1, BAX, BCL2-associated X protein, BCL2, B-cell CLL/lymphoma 2 protein, CALR, calreticulin, CTL, cytotoxic T lymphocyte, DAMP, damage-associated molecular pattern, DAPI, 4′,6-diamidino-2-phenylindole, DiOC6(3), 3,3′-dihexyloxacarbocyanine iodide, EIF2A, eukaryotic translation initiation factor 2A, ER, endoplasmic reticulum, FLT3LG, fms-related tyrosine kinase 3 ligand, G3BP1, GTPase activating protein (SH3 domain) binding protein 1, GFP, green fluorescent protein, H2B, histone 2B, HMGB1, HMGB1, high mobility group box 1, HSP, heat shock protein, HSV-1, herpes simplex virus type I, ICD, immunogenic cell death, IFN, interferon, IL, interleukin, MOMP, mitochondrial outer membrane permeabilization, PDIA3, protein disulfide isomerase family A, PI, propidium iodide, RFP, red fluorescent protein, TLR, Toll-like receptor, XBP1, X-box binding protein 1, autophagy, calreticulin, endoplasmic reticulum stress, immunotherapy, member 3, Δψm, mitochondrial transmembrane potential,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH