scholarly journals Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity

2019 ◽  
Vol 4 (36) ◽  
pp. eaaw2004 ◽  
Author(s):  
Annelise G. Snyder ◽  
Nicholas W. Hubbard ◽  
Michelle N. Messmer ◽  
Sigal B. Kofman ◽  
Cassidy E. Hagan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
De Novo ◽  
Immune Checkpoint Blockade ◽  
Treatment Modalities ◽  
Interacting Protein ◽  
Multiple Treatment ◽  
Proinflammatory Mediators ◽  
Dying Cells

Although the signaling events that induce different forms of programmed cell death are well defined, the subsequent immune responses to dying cells in the context of cancer remain relatively unexplored. Necroptosis occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3, whose activation leads to lytic cell death accompanied by de novo production of proinflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3+ cDC1− and CD8+ leukocyte–dependent antitumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen-presenting cells. Furthermore, we report the development of constitutively active forms of the necroptosis-inducing enzyme RIPK3 and show that delivery of a gene encoding this enzyme to tumor cells using adeno-associated viruses induces tumor cell necroptosis, which synergizes with immune checkpoint blockade to promote durable tumor clearance. These findings support a role for RIPK1/RIPK3 activation as a beneficial proximal target in the initiation of tumor immunity. Considering that successful tumor immunotherapy regimens will require the rational application of multiple treatment modalities, we propose that maximizing the immunogenicity of dying cells within the tumor microenvironment through specific activation of the necroptotic pathway represents a beneficial treatment approach that may warrant further clinical development.

scholarly journals Carcinogenesis-relevant biological events in the pathophysiology of the efferocytosis phenomenon

2017 ◽  
Author(s):  
Gargi Sachin Sarode ◽  
Sachin C. Sarode ◽  
Nikunj Maniyar ◽  
Nilesh Kumar Sharma ◽  
Shankargouda Patil
Keyword(s):  
Wound Healing ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
Tissue Repair ◽  
Antitumor Immunity ◽  
Surrounding Tissue ◽  
Effective Removal ◽  
Immunosuppressive Action ◽  
Dying Cells

The effective removal of cells undergoing programmed cell death, which is referred to as efferocytosis, prevents the leakage of intracellular contents into the surrounding tissue, which could lead to tissue damage and inflammation. Efferocytosis involves a coordinated orchestration of multiple steps that lead to a swift, coherent and immunologically silent removal of dying cells. The release of wound healing cytokines, which resolve inflammation and enhance tissue repair, is an important feature of efferocytosis. However, in addition to the healing cytokines released during efferocytosis, the immunosuppressive action of cytokines promotes the tumor microenvironment, enhances the motility of cancer cells and promotes the evasion of antitumor immunity. The aim of the present review was to comprehensively discuss the efferocytosis phenomenon, the important players associated with this process and their role in cancer-related biological events.

scholarly journals KALRN mutations promote antitumor immunity and immunotherapy response in cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000293
Author(s):  
Mengyuan Li ◽  
Yuxiang Ma ◽  
You Zhong ◽  
Qian Liu ◽  
Canping Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Patients With Cancer ◽  
In Vivo Experiments ◽  
Damage Repair

Backgroundkalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.MethodsWe explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.ResultsAntitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.ConclusionsThe KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.

scholarly journals Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Wenjing Qian ◽  
Mingfang Zhao ◽  
Ruoyu Wang ◽  
Heming Li
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Escape ◽  
De Novo ◽  
Lymphocyte Activation ◽  
Response Prediction ◽  
Immune Checkpoint Blockade ◽  
Mesenchymal Transition

AbstractImmune checkpoint therapy has achieved significant efficacy by blocking inhibitory pathways to release the function of T lymphocytes. In the clinic, anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) have progressed to first-line monotherapies in certain tumor types. However, the efficacy of anti-PD-1/PD-L1 mAbs is still limited due to toxic side effects and de novo or adaptive resistance. Moreover, other immune checkpoint target and biomarkers for therapeutic response prediction are still lacking; as a biomarker, the PD-L1 (CD274, B7-H1) expression level is not as accurate as required. Hence, it is necessary to seek more representative predictive molecules and potential target molecules for immune checkpoint therapy. Fibrinogen-like protein 1 (FGL1) is a proliferation- and metabolism-related protein secreted by the liver. Multiple studies have confirmed that FGL1 is a newly emerging checkpoint ligand of lymphocyte activation gene 3 (LAG3), emphasizing the potential of targeting FGL1/LAG3 as the next generation of immune checkpoint therapy. In this review, we summarize the substantial regulation mechanisms of FGL1 in physiological and pathological conditions, especially tumor epithelial to mesenchymal transition, immune escape and immune checkpoint blockade resistance, to provide insights for targeting FGL1 in cancer treatment.

scholarly journals Pyroptotic and Necroptotic Cell Death in the Tumor Microenvironment and Their Potential to Stimulate Anti-Tumor Immune Responses

2021 ◽  
Vol 11 ◽  
Author(s):  
Allan Scarpitta ◽  
Ulrich T. Hacker ◽  
Hildegard Büning ◽  
Olivier Boyer ◽  
Sahil Adriouch
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Immune Cells ◽  
Immunogenic Cell Death ◽  
Chemotherapeutic Drugs ◽  
Immune Functions ◽  
Molecular Patterns ◽  
Dying Cells ◽  
Damage Associated Molecular Patterns

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.

scholarly journals Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

2017 ◽  
Vol 114 (6) ◽  
pp. E961-E969 ◽  
Author(s):  
Stephanie A. Conos ◽  
Kaiwen W. Chen ◽  
Dominic De Nardo ◽  
Hideki Hara ◽  
Lachlan Whitehead ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Adaptor Protein ◽  
Cell Lysis ◽  
Kinase Domain ◽  
Receptor Protein ◽  
Interacting Protein ◽  
Caspase 1 ◽  
Proinflammatory Mediators ◽  
Death Effector

Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKL-induced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKL-dependent diseases.

scholarly journals Induction of necrotic cell death and activation of STING in the tumor microenvironment via cationic silica nanoparticles leading to enhanced antitumor immunity

Nanoscale ◽  
2018 ◽  
Vol 10 (19) ◽  
pp. 9311-9319 ◽  
Author(s):  
Myunggi An ◽  
Chunsong Yu ◽  
Jingchao Xi ◽  
Joyce Reyes ◽  
Guangzhao Mao ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Silica Nanoparticles ◽  
Antitumor Immunity ◽  
Intratumoral Injection ◽  
Necrotic Cell Death ◽  
Necrotic Cell

Potent antitumor immunity is induced by intratumoral injection of cytotoxic silica nanoparticles complexed with a STING agonist.

scholarly journals IMMU-03. SUPPRESSION OF ONCOMETABOLITE 2-HYDROXYGLUTRATE PRODUCED BY MUTANT IDH1 GLIOMA WITH AGI-5198 ENHANCES THE EFFICACY OF RADIOTHERAPY AND IMMUNE CHECKPOINT BLOCKADE ELICITING IMMUNOLOGICAL MEMORY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi119-vi119
Author(s):  
Padma Kadiyala ◽  
Felipe Nunez ◽  
Maria Garcia-Fabiani ◽  
Fernando Nunez ◽  
Dan Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immunological Memory ◽  
Prognostic Indicator ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Low Grade ◽  
Enzymatic Function ◽  
Mutant Idh1

Abstract Patients with mutant IDH1 gliomas survive ~3.8 year longer than patients harboring wildtype IDH1 glioma, irrespective of histology or genetic lesions, making mutant IDH1 an essential prognostic indicator. Mutant IDH1 gliomas are highly infiltrative with a high incidence of relapse. We are studying a low grade glioma subtype, genetically characterized by inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, TP53 and gain of function mutations in isocitrate dehyrdogenase 1 (mIDH1). Mutation in IDH1 converts α-ketoglutrate (αKG) to 2-hydroxyglutarate (2HG), an oncometabolite that inhibits histone and DNA demethylases, leading to a hypermethylated tumor phenotype [1]. This leads to epigenetic reprograming of the tumor transcriptome. The role of 2HG as an immune regulator in the mIDH1 glioma tumor microenvironment remains to be elucidated. Herein, we investigate whether 2HG produced by mIDH1 glioma in the tumor microenvironment mediating antitumor immunity. We used mIDH1 inhibitor AGI-5198 to abrogate the neomorphic enzymatic activity of IDH1R132H in a transplantable mIDH1 glioma mouse model. Animals were implanted with mIDH1 tumor neurospheres and they were systemically administered with AGI-5198. Our results indicate that pharmacological inhibition of IDH1R132H enzymatic function significantly prolongs the median survival (MS) of mIDH1 glioma bearing mice (~1.5-fold vs controls); eliciting strong antitumor activity, eradicating 40% of the established mIDH1 gliomas. Our results also demonstrate that antitumor immunity induced by 2HG inhibition is enhanced when combined with standard of care (temozolomide and radiation) and anti-PDL1 immune checkpoint blockade. In addition, when the long-term survivors (>90 days) were rechallenged with mIDH1 tumor cells in the contralateral hemisphere, without further treatment, all the mice remained tumor free, indicating the development of anti-glioma immunological memory. Collectively, these findings support the clinical testing of AGI-5198 as an adjuvant therapy and a novel immunotherapeutic strategy for treating patients with mIDH1 glioma.

Potential and unsolved problems of anti-PD-1/PD-L1 therapy combined with radiotherapy

2020 ◽  
pp. 030089162094038
Author(s):  
Yiyi Cao ◽  
Wenbo Li ◽  
ZhengJie Wang ◽  
Hua Pang
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Radiation Therapy ◽  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
Death Receptor ◽  
Anticancer Therapy ◽  
Primary Resistance ◽  
Patients With Cancer ◽  
Cell Death Receptor

Tumor immunotherapy has become one of the main treatments for tumors. Inhibition of the pathways involving programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) has gained favor in anticancer therapy, and can effectively prolong the survival of patients with cancer; however, numerous patients have PD-1/PD-L1 inhibitor primary resistance. The efficacy of anti-PD-1/PD-L1 therapy is related to the host tumor microenvironment. Radiation therapy can promote the body’s antitumor immunity, change the tumor microenvironment, and synergize with anti-PD-1/PD-L1 treatment. Preclinical and clinical trials have shown that PD-1/PD-L1 inhibitor combined with radiotherapy has a significant effect. We review the synergistic antitumor mechanism and clinical trials of radiotherapy combined with anti-PD-1/PD-L1 therapy.

scholarly journals Bortezomib enhances dendritic cell (DC)–mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4839-4845 ◽  
Author(s):  
Radek Spisek ◽  
Anna Charalambous ◽  
Amitabha Mazumder ◽  
David H. Vesole ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Heat Shock Protein 90 ◽  
Human Tumors ◽  
Tumor Cell Death ◽  
Dying Cells

Abstract Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death. Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors, including myeloma. Here we show that the uptake of human myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not γ irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants. The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (an hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These data identify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors. Specific targeting of bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.

scholarly journals Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death

Oncogene ◽  
2003 ◽  
Vol 22 (47) ◽  
pp. 7396-7402 ◽  
Author(s):  
Lori A Hazlehurst ◽  
Terry H Landowski ◽  
William S Dalton
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
De Novo ◽  
De Novo Resistance
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