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.

• Keywords
• immunology, molecular biology, oncology,
• MeSH
• Immunogenic Cell Death genetics   MeSH
• Consensus MeSH
• Humans MeSH
• Molecular Biology methods   MeSH
• Guidelines as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review 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.

• Keywords
• Antigen-presenting cell, CAR T cells, autophagy, chemokines, cytokines, cytotoxic T lymphocyte, dendritic cell, endoplasmic reticulum stress, immune checkpoint blocker, type I interferon,
• MeSH
• Adaptive Immunity MeSH
• Immunogenic Cell Death MeSH
• Immunotherapy MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antineoplastic Agents * MeSH

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, and defects in DC functions contribute to the pathogenesis of a variety of disorders. For instance, cancer evolves in the context of limited DC activity, and some autoimmune diseases are initiated by DC-dependent antigen presentation. Thus, correcting aberrant DC functions stands out as a promising therapeutic paradigm for a variety of diseases, as demonstrated by an abundant preclinical and clinical literature accumulating over the past two decades. However, the therapeutic potential of DC-targeting approaches remains to be fully exploited in the clinic. Here, we discuss the unique features of DCs that underlie the high therapeutic potential of DC-targeting strategies and critically analyze the obstacles that have prevented the full realization of this promising paradigm.

• Keywords
• autoimmune disorders, cancer, dendritic cells, immunotherapy, vaccine preparation,
• MeSH
• Antigen-Presenting Cells immunology   metabolism   MeSH
• Autoimmunity MeSH
• Autoimmune Diseases etiology   metabolism   therapy   MeSH
• Cell Differentiation genetics   immunology   MeSH
• Dendritic Cells immunology   metabolism   MeSH
• Immunity * MeSH
• Immune Tolerance * MeSH
• Immunotherapy MeSH
• Humans MeSH
• Cell Communication MeSH
• Disease Susceptibility MeSH
• Neoplasms etiology   metabolism   pathology   therapy   MeSH
• Cell Plasticity genetics   immunology   MeSH
• Antigen Presentation immunology   MeSH
• Cancer Vaccines administration & dosage   immunology   MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cancer Vaccines MeSH

Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.

• Keywords
• Ampligen®, Hiltonol®, SD-101, bacillus Calmette-Guérin, imiquimod, motolimod,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.

• Keywords
• CAR T cells, MAGEA3, NY-ESO-1, immune checkpoint blockers, mutational load, synthetic long peptides, tumor neoantigens,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Cytokines regulate virtually aspects of innate and adaptive immunity, including the initiation, execution and extinction of tumor-targeting immune responses. Over the past three decades, the possibility of using recombinant cytokines as a means to elicit or boost clinically relevant anticancer immune responses has attracted considerable attention. However, only three cytokines have been approved so far by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, namely, recombinant interleukin (IL)-2 and two variants of recombinant interferon alpha 2 (IFN-α2a and IFN-α2b). Moreover, the use of these cytokines in the clinics is steadily decreasing, mostly as a consequence of: (1) the elevated pleiotropism of IL-2, IFN-α2a and IFN-α2b, resulting in multiple unwarranted effects; and (2) the development of highly effective immunostimulatory therapeutics, such as immune checkpoint blockers. Despite this and other obstacles, research in the field continues as alternative cytokines with restricted effects on specific cell populations are being evaluated. Here, we summarize research preclinical and clinical developments on the use of recombinant cytokines for immunostimulation in cancer patients.

• Keywords
• CAR T cells, CTLA4, GM-CSF, IL-15, PD-1, pembrolizumab,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review 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.

• Keywords
• Caspases, ER stress, ecto-CALR, high hydrostatic pressure, immunogenic cell death,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Leukemia, Myeloid, Acute drug therapy   genetics   immunology   metabolism   MeSH
• Alarmins metabolism   MeSH
• Blast Crisis immunology   pathology   MeSH
• Cell Death MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Phenotype MeSH
• Transcription, Genetic MeSH
• Immunity MeSH
• Calreticulin metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Multivariate Analysis MeSH
• Proportional Hazards Models MeSH
• HSP70 Heat-Shock Proteins metabolism   MeSH
• HSP90 Heat-Shock Proteins metabolism   MeSH
• Gene Expression Regulation, Leukemic MeSH
• Gene Expression Profiling MeSH
• Th1 Cells immunology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alarmins MeSH
• CALR protein, human MeSH Browser
• Calreticulin MeSH
• HSP70 Heat-Shock Proteins MeSH
• HSP90 Heat-Shock Proteins MeSH