Immunology of Cell Death in Cancer Immunotherapy.
TL;DR: A large volume of studies has established that dying and dead cancer cells exert a potent immunomodulatory effect on their immediate microenvironment, which has a major influence on the anticancer immunity as discussed by the authors.
Abstract: Over the last two decades, a large volume of studies has established that dying and dead cancer cells exert a potent immunomodulatory effect on their immediate microenvironment, which has a major influence on the anticancer immunity [...].
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TL;DR: This review describes what is currently known about granzyme structure, processing, and granzyme-induced cell death in the context of cancer and in some other inflammatory diseases.
Abstract: Cytotoxic T lymphocytes, differentiated CD8+ T cells, use multiple mechanisms to mediate their function, including release of granules containing perforin and granzymes at target cells. Granzymes are a family of cytotoxic proteases that each act on unique sets of biological substrates within target cells, usually to induce cell death. Granzymes are differentially expressed within T cells, depending on their environment and activation state, making the granzyme cytotoxic pathway dynamic and responsive to individual circumstances. In this review, we describe what is currently known about granzyme structure, processing, and granzyme-induced cell death in the context of cancer and in some other inflammatory diseases.
14 citations
TL;DR: Wang et al. as discussed by the authors developed and validated an effective signature based on autophagy-, apoptosis-and necrosis-related genes for prognostic implications in Glioblastoma (GBM) patients.
Abstract: Glioblastoma (GBM) is considered the most malignant and devastating intracranial tumor without effective treatment. Autophagy, apoptosis, and necrosis, three classically known cell death pathways, can provide novel clinical and immunological insights, which may assist in designing personalized therapeutics. In this study, we developed and validated an effective signature based on autophagy-, apoptosis- and necrosis-related genes for prognostic implications in GBM patients.Variations in the expression of genes involved in autophagy, apoptosis and necrosis were explored in 518 GBM patients from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were performed to construct a combined prognostic signature. Kaplan-Meier survival, receiver-operating characteristic (ROC) curves and Cox regression analyses based on overall survival (OS) and progression-free survival (PFS) were conducted to estimate the independent prognostic performance of the gene signature. The Chinese Glioma Genome Atlas (CGGA) dataset was used for external validation. Finally, we investigated the differences in the immune microenvironment between different prognostic groups and predicted potential compounds targeting each group.A 16-gene cell death index (CDI) was established. Patients were clustered into either the high risk or the low risk groups according to the CDI score, and those in the low risk group presented significantly longer OS and PFS than the high CDI group. ROC curves demonstrated outstanding performance of the gene signature in both the training and validation groups. Furthermore, immune cell analysis identified higher infiltration of neutrophils, macrophages, Treg, T helper cells, and aDCs, and lower infiltration of B cells in the high CDI group. Interestingly, this group also showed lower expression levels of immune checkpoint molecules PDCD1 and CD200, and higher expression levels of PDCD1LG2, CD86, CD48 and IDO1.Our study proposes that the CDI signature can be utilized as a prognostic predictor and may guide patients' selection for preferential use of immunotherapy in GBM.
8 citations
TL;DR: Wang et al. as discussed by the authors developed and validated an effective signature based on autophagy-, apoptosis-and necrosis-related genes for prognostic implications in Glioblastoma (GBM) patients.
Abstract: Glioblastoma (GBM) is considered the most malignant and devastating intracranial tumor without effective treatment. Autophagy, apoptosis, and necrosis, three classically known cell death pathways, can provide novel clinical and immunological insights, which may assist in designing personalized therapeutics. In this study, we developed and validated an effective signature based on autophagy-, apoptosis- and necrosis-related genes for prognostic implications in GBM patients.Variations in the expression of genes involved in autophagy, apoptosis and necrosis were explored in 518 GBM patients from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were performed to construct a combined prognostic signature. Kaplan-Meier survival, receiver-operating characteristic (ROC) curves and Cox regression analyses based on overall survival (OS) and progression-free survival (PFS) were conducted to estimate the independent prognostic performance of the gene signature. The Chinese Glioma Genome Atlas (CGGA) dataset was used for external validation. Finally, we investigated the differences in the immune microenvironment between different prognostic groups and predicted potential compounds targeting each group.A 16-gene cell death index (CDI) was established. Patients were clustered into either the high risk or the low risk groups according to the CDI score, and those in the low risk group presented significantly longer OS and PFS than the high CDI group. ROC curves demonstrated outstanding performance of the gene signature in both the training and validation groups. Furthermore, immune cell analysis identified higher infiltration of neutrophils, macrophages, Treg, T helper cells, and aDCs, and lower infiltration of B cells in the high CDI group. Interestingly, this group also showed lower expression levels of immune checkpoint molecules PDCD1 and CD200, and higher expression levels of PDCD1LG2, CD86, CD48 and IDO1.Our study proposes that the CDI signature can be utilized as a prognostic predictor and may guide patients' selection for preferential use of immunotherapy in GBM.
7 citations
TL;DR: In this paper , peritoneal macrophages (Ma), obtained from Fisher rats acting as APCs, were co-incubated with dead F98 glioma cells killed via DOX or DOX-PCI treatment ex vivo.
3 citations
TL;DR: An innovative prognostic signature based on necroptosis-related lncRNAs was developed for LUAD through comprehensive bioinformatics analysis, which can act as a predictor of immunotherapy and may provide guidance for clinicians.
Abstract: Background: As a new style of cell death, necroptosis plays a crucial role in tumor immune microenvironment. LncRNAs have been identified to act as competitive RNAs to influence genes involved in necroptosis. Therefore, we aim to create a signature based on necroptosis-related lncRNAs to predict the prognosis and immune landscape of lung adenocarcinoma (LUAD) patients in this study. Methods: TCGA database was used to acquire RNA sequencing (RNA-Seq) data and clinical information for 59 lung normal samples and 535 lung adenocarcinoma samples. The Pearson correlation analysis, univariate cox regression analysis and least absolute shrinkage and selection operator (LASSO) cox regression were performed to construct the prognostic NRlncRNAs signature. Then we used Kaplan-Meier (K-M) analysis, time-dependent ROC curves, univariate and multivariate cox regression analysis, and nomogram to validate this signature. In addition, GO, KEGG, and GSVA were analyzed to investigate the potential molecular mechanism. Moreover, we analyzed the relationship between our identified signature and immune microenvironment, TMB, and some clinical characteristics. Finally, we detected the expression of the six necroptosis-related lncRNAs in cells and tissues. Results: We constructed a NRlncRNAs signature consisting of six lncRNAs (FRMD6-AS1, LINC01480, FAM83A-AS1, FRMD6-AS1, MED4-AS1, and LINC01415) in LUAD. LUAD patients with high risk scores had lower chance of survival with an AUC of 0.739, 0.709, and 0.733 for 1-year, 3-year, and 5-year respectively. The results based on GO, KEGG, and GSVA enrichment analysis demonstrated that NRlncRNAs signature-related genes were mainly correlated with immune pathways, metabolic-and cell growth-related pathways, cell cycle, and apoptosis. Moreover, the risk score was correlated with the immune status of LUAD patients. Patients with higher risk scores had lower ESTIMATE scores and higher TIDE scores. The risk score was positively correlated with TMB. LINC01415, FRMD6-AS1 and FAM83A-AS1 were significantly overexpressed in lung adenocarcinoma, while the expression levels of MED4-AS1 and LINC01480 were lower in lung adenocarcinoma. Conclusion: Overall, an innovative prognostic signature based on NRlncRNAs was developed for LUAD through comprehensive bioinformatics analysis, which can act as a predictor of immunotherapy and may provide guidance for clinicians.
3 citations
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Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
TL;DR: Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins.
Abstract: Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
2,003 citations
TL;DR: A panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours is provided and the impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
Abstract: Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.
1,680 citations
TL;DR: This Review highlights recent advances in the understanding of the complex regulation of the mTOR pathway and discusses its function in the context of physiology, human disease and pharmacological intervention.
Abstract: The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.
1,253 citations
TL;DR: How different DC subsets influence immunity and tolerance in cancer settings is outlined and the implications for both established cancer treatments and novel immunotherapy strategies are discussed.
Abstract: Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.
1,117 citations