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Open accessJournal ArticleDOI: 10.1080/2162402X.2021.1893466

Tumor-intrinsic determinants of immunogenic cell death modalities

02 Mar 2021-OncoImmunology (Informa UK Limited)-Vol. 10, Iss: 1, pp 1893466-1893466
Abstract: The immune system can recognize tumor cells to mount antigen-specific T cell response. Central to the establishment of T cell-mediated adaptive immunity are the inflammatory events that facilitate antigen presentation by stimulating the expression of MHC and costimulatory molecules and the secretion of pro-inflammatory cytokines. Such inflammatory events can be triggered upon cytotoxic treatments that induce immunogenic cancer cell death modalities. However, cancers have acquired a plethora of mechanisms to subvert, or to hide from, host-encoded immunosurveillance. Here, we discuss how tumor intrinsic oncogenic factors subvert desirable intratumoral inflammation by suppressing immunogenic cell death.

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Topics: Immunogenic cell death (64%), Acquired immune system (55%), Cytotoxic T cell (55%) ... show more
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5 results found


Open accessJournal ArticleDOI: 10.1111/ODI.14077
Yu-Yue Zhao1, Jun-Xiang Lian1, Zhou Lan1, Ke-Long Zou1  +2 moreInstitutions (2)
12 Nov 2021-Oral Diseases
Abstract: Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.

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Open accessJournal ArticleDOI: 10.3389/FONC.2021.731598
Abstract: Cancer remains the second most common cause of death worldwide affecting around 10 million patients every year. Among the therapeutic options, chemotherapeutic drugs are widely used but often associated with side effects. In addition, toxicity against immune cells may hamper anti-tumor immune responses. Some chemotherapeutic drugs, however, preserve immune functions and some can even stimulate anti-tumor immune responses through the induction of immunogenic cell death (ICD) rather than apoptosis. ICD stimulates the immune system by several mechanisms including the release of damage-associated molecular patterns (DAMPs) from dying cells. In this review, we will discuss the consequences of inducing two recently characterized forms of ICD, i.e., pyroptosis and necroptosis, in the tumor microenvironment (TME) and the perspectives they may offer to increase the immunogenicity of the so-called cold tumors and to stimulate effective anti-tumor immune responses.

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Topics: Immunogenic cell death (60%), Pyroptosis (58%), Necroptosis (57%) ... show more

Open accessJournal ArticleDOI: 10.1016/J.COI.2021.10.004
Abstract: Adoptive T cell therapy (ACT) with tumor-reactive lymphocytes can overcome the immune desert of poorly immunogenic tumors and instruct tumor eradication. Several hurdles limit the efficacy of this strategy against solid tumor including, but not limited to, sub optimal T cell engraftment, tumor infiltration, poor tumor antigenicity/immunogenicity, and immunosuppressive or resistance mechanisms. Recent advances indicate that concomitant treatments can be set in place to offset such barriers. In this review, we highlight the beneficial effects of combining ACT with conventional chemo and/or radiotherapy. While originally classified as immunosuppressive, these methodologies can also promote the engraftment of ACT products, immunogenic cell death, and the reprogramming of more favorable microenvironments. Data indicates that systemic and local chemo/radiotherapy regimens promote intratumoral cytokine and chemokine upregulation, tumor antigen presentation and cross presentation, infiltration and in situ T cells reactivation. Here we review the most recent contributions supporting these notions and discuss further developments.

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Topics: Immunogenic cell death (58%), Tumor antigen (57%), T cell (52%)

Open accessJournal ArticleDOI: 10.3390/CELLS10051208
Lorenzo Galluzzi1, Abhishek D. Garg2Institutions (2)
15 May 2021-Cells
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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Topics: Necroptosis (57%), Cancer immunotherapy (56%), Cancer cell (52%)

Book ChapterDOI: 10.1016/B978-0-12-814208-0.00008-7
Daiqing Liao1Institutions (1)
01 Jan 2022-
Abstract: Regulated cell death (RCD) plays important roles in health and diseases. The molecular mechanisms underlying several major forms of RCD including apoptosis, necroptosis, and pyroptosis have been well defined. They are triggered by distinct cell death stimuli, operate through separate intracellular machinery, and exert different physiological impacts. These forms of cell death are also intricately interconnected. The roles of these cell death modalities in normal physiology and pathophysiology have been extensively studied. Resistance to apoptosis underlies tumorigenesis and failure of cancer therapy, whereas dysregulated necroptosis and pyroptosis are implicated in diverse pathologies ranging from infectious diseases, acute and chronic inflammation, and cancer etiology and progression. The discovery of key players in RCD pathways provides ample molecular targets for drug developments for treating a broad spectrum of diseases. Apoptosis is regarded as the major form of RCD during animal development and the maintenance of homeostasis. Caspase-dependent apoptosis is estimated to account for about 90% of billions of cell death events in homeostasis. Apoptosis has been a major focus of drug discovery for many years, resulting in the approval of the BCL-2 inhibitor ABT-199 (also known as venclexta and venetoclax) by the Food and Drug Administration for treating CLL (chronic lymphocytic leukemia) and SLL (small lymphocytic lymphoma) in 2016, and many drug candidates targeting apoptosis are in clinical studies. Necroptosis and pyroptosis are lytic form of RCD triggered by infections with pathogens and in response to inflammatory stimuli. Necroptotic and pyroptotic cells release cellular contents known as damage-associated molecular patterns as well as intracellular pathogens in infected cells and associated products known as pathogen-associated molecular patterns which lead to further inflammation. Understanding of the molecular mechanisms underlying necroptosis and pyroptosis has attracted resurgent research interests and some key regulators and their functional roles have been identified and defined in recent years. Because of implications of necroptosis and pyroptosis in diverse human diseases, the development of agents that block or activate necroptosis and pyroptosis has gained intense interest aimed at treating different diseases ranging from inflammatory maladies, infectious diseases to cancer. This chapter succinctly summarizes the key molecular features of apoptosis, necroptosis, and pyroptosis, their dysregulation in human diseases, and major small molecule inhibitors and biologics that modulate these forms of cell death for therapeutic applications.

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Topics: Necroptosis (69%), Pyroptosis (63%), Programmed cell death (51%)
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177 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.02.013
Douglas Hanahan1, Robert A. Weinberg2Institutions (2)
04 Mar 2011-Cell
Abstract: The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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42,275 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1003466
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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Topics: Ipilimumab (61%), Pembrolizumab (57%), Nivolumab (57%) ... show more

11,659 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1235122
29 Mar 2013-Science
Abstract: Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

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Topics: Carcinogenesis (54%), Cancer (54%), Genome (52%) ... show more

5,607 Citations


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)81902-9
Manuel Serrano1, Athena W. Lin1, Mila E. McCurrach1, David Beach2  +2 moreInstitutions (2)
07 Mar 1997-Cell
Abstract: Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.

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Topics: Stress-induced premature senescence (66%), Cell aging (56%), Senescence (54%) ... show more

4,485 Citations


Journal ArticleDOI: 10.1126/SCIENCE.1203486
25 Mar 2011-Science
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

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Topics: Immunoediting (59%), Tumor progression (56%), Tumor microenvironment (53%) ... show more

4,153 Citations


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