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

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 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

The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development.

• Klíčová slova
• ATP, Adenosine triphosphate, CRT, calreticulin, DAMPs, danger-associated molecular patterns, DC, dendritic cells, EGFR, endothelial growth factor receptor, ER, endoplasmic reticulum, HHP, high hydrostatic pressure, HMGB1, high-mobility group box 1, HSP, heat shock protein, HT, hyperthermia, Hyp-PDT, Hypericin-based Photodynamic therapy, ICD, immunogenic cell death, IFNγ, interferon-γ, NDV, Newcastle Disease Virus, ROS, reactive oxygen species, RT, radiotherapy, TLR, Toll-like receptor, UVC, ultraviolet C light, cancer immunotherapy, eIF2α, eukaryotic translation initiation factor 2α, high hydrostatic pressure, hyperthermia, immunogenic cell death, ionizing irradiation, photodynamic therapy with hypericin,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH