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Immune checkpoint inhibitor-associated hypophysitis-World Health Organisation VigiBase report analysis.
Guerrero E, Johnson DB, Bachelot A, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 113: 10-13
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Databases, Factual, Female, Humans, Hypophysitis, Ipilimumab, Male, Middle Aged, Nivolumab, Pharmacovigilance, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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20 MeSH Terms
Hematologic Complications of Immune Checkpoint Inhibitors.
Davis EJ, Salem JE, Young A, Green JR, Ferrell PB, Ancell KK, Lebrun-Vignes B, Moslehi JJ, Johnson DB
(2019) Oncologist 24: 584-588
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, Databases, Factual, Female, Hematologic Diseases, Humans, Incidence, Ipilimumab, Male, Middle Aged, Neoplasms, Pharmacovigilance, Programmed Cell Death 1 Receptor, Risk Factors
Show Abstract · Added November 12, 2019
Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP ( = 68) and HA ( = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days,  = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.
© AlphaMed Press 2019.
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19 MeSH Terms
Response to Anti-PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis.
Johnson DB, Bao R, Ancell KK, Daniels AB, Wallace D, Sosman JA, Luke JJ
(2019) J Natl Compr Canc Netw 17: 114-117
MeSH Terms: Antineoplastic Agents, Immunological, Computational Biology, Gene Expression Profiling, Humans, Liver Neoplasms, Melanoma, Molecular Targeted Therapy, Neoplasm Staging, Prognosis, Programmed Cell Death 1 Receptor, Treatment Outcome, Uveal Neoplasms
Show Abstract · Added March 30, 2020
Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti-PD-1 in this setting and to understand the mutational and immunologic profile of this disease. A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with pathway overexpression. Anti-PD-1-based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and overexpression may be factors limiting therapeutic responses. NCT02359851.
Copyright © 2019 by the National Comprehensive Cancer Network.
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12 MeSH Terms
Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8 T cells.
Gemta LF, Siska PJ, Nelson ME, Gao X, Liu X, Locasale JW, Yagita H, Slingluff CL, Hoehn KL, Rathmell JC, Bullock TNJ
(2019) Sci Immunol 4:
MeSH Terms: Animals, Antineoplastic Agents, Immunological, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Glucose, Glucose Transporter Type 1, Glycolysis, Hepatitis A Virus Cellular Receptor 2, Humans, Immunoglobulin G, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, Melanoma, Mice, Inbred C57BL, Phosphopyruvate Hydratase, Programmed Cell Death 1 Receptor
Show Abstract · Added March 30, 2020
In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8 tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8 TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8 melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8 TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8 TILs. We found high expression of both enolase 1 mRNA and protein in CD8 TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8 TIL dysfunction.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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16 MeSH Terms
Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
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15 MeSH Terms
Small Cell Lung Cancer Transformation as a Mechanism of Resistance to PD-1 Therapy in KRAS-Mutant Lung Adenocarcinoma: A Report of Two Cases.
Iams WT, Beckermann KE, Almodovar K, Hernandez J, Vnencak-Jones C, Lim LP, Raymond CK, Horn L, Lovly CM
(2019) J Thorac Oncol 14: e45-e48
MeSH Terms: Adenocarcinoma of Lung, Aged, Antineoplastic Agents, Immunological, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Mutation, Prognosis, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), Small Cell Lung Carcinoma
Added September 10, 2020
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PD-1 up-regulation on CD4 T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.
Celada LJ, Kropski JA, Herazo-Maya JD, Luo W, Creecy A, Abad AT, Chioma OS, Lee G, Hassell NE, Shaginurova GI, Wang Y, Johnson JE, Kerrigan A, Mason WR, Baughman RP, Ayers GD, Bernard GR, Culver DA, Montgomery CG, Maher TM, Molyneaux PL, Noth I, Mutsaers SE, Prele CM, Peebles RS, Newcomb DC, Kaminski N, Blackwell TS, Van Kaer L, Drake WP
(2018) Sci Transl Med 10:
MeSH Terms: Adult, Aged, Animals, Bleomycin, CD4-Positive T-Lymphocytes, Cell Proliferation, Collagen Type I, Disease Models, Animal, Female, Fibroblasts, Gene Expression Regulation, Humans, Idiopathic Pulmonary Fibrosis, Interleukin-17, Male, Mice, Middle Aged, Programmed Cell Death 1 Receptor, RNA, Messenger, STAT3 Transcription Factor, Sarcoidosis, Th17 Cells, Transforming Growth Factor beta1, Up-Regulation
Show Abstract · Added March 26, 2019
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1CD4 T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4 T cells. PD-1 T helper 17 cells are the predominant CD4 T cell subset expressing TGF-β. Coculture of PD-1CD4 T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4 T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1CD4 T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms
Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma.
Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, Ganesan S, Bhanot G, Rathmell WK
(2018) JCI Insight 3:
MeSH Terms: Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, B7-H1 Antigen, Carcinoma, Renal Cell, Datasets as Topic, Drug Resistance, Neoplasm, Endogenous Retroviruses, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Male, Middle Aged, Programmed Cell Death 1 Receptor, Progression-Free Survival, Retrospective Studies, Sequence Analysis, RNA
Show Abstract · Added October 30, 2019
Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-low ccRCC tumors. Similar results were observed in ER+/HER2- breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and πERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.
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Reporting of immune checkpoint inhibitor-associated myocarditis - Authors' reply.
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB
(2018) Lancet 392: 384-385
MeSH Terms: Antibodies, Monoclonal, Humans, Myocarditis, Programmed Cell Death 1 Receptor
Added October 1, 2018
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MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.
Dovey CM, Diep J, Clarke BP, Hale AT, McNamara DE, Guo H, Brown NW, Cao JY, Grace CR, Gough PJ, Bertin J, Dixon SJ, Fiedler D, Mocarski ES, Kaiser WJ, Moldoveanu T, York JD, Carette JE
(2018) Mol Cell 70: 936-948.e7
MeSH Terms: Binding Sites, Cell Death, Colonic Neoplasms, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, Herpesvirus 1, Human, Humans, Inositol Phosphates, Jurkat Cells, Mutation, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added March 30, 2020
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Copyright © 2018 Elsevier Inc. All rights reserved.
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