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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
0 Communities
1 Members
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MeSH Terms
A Critical Need for Better Cancer Immunotherapy Models: Are Organotypic Tumor Spheroid Cultures the Answer?
Balko JM, Sosman JA
(2018) Cancer Discov 8: 143-145
MeSH Terms: Animals, Humans, Immunotherapy, Mice, Neoplasms, Programmed Cell Death 1 Receptor
Show Abstract · Added March 14, 2018
Immunotherapy has transformed the therapeutic landscape of cancer, but the preclinical evaluation of combination approaches that will deepen and broaden its clinical benefit has lagged far behind due to the lack of expedient and easily accessible human systems. In this issue, Jenkins and colleagues and Deng and colleagues report the use of organotypic cultures of tumors derived from mice and humans containing both tumor cells and cells from their local immune microenvironment to recapitulate the use of immune checkpoint inhibitors and extend the application of this system to therapeutic combinations of immune checkpoint blockade and molecularly targeted agents. .
©2018 American Association for Cancer Research.
0 Communities
1 Members
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6 MeSH Terms
Quantitative Mass Spectrometry Analysis of PD-L1 Protein Expression, -glycosylation and Expression Stoichiometry with PD-1 and PD-L2 in Human Melanoma.
Morales-Betanzos CA, Lee H, Gonzalez Ericsson PI, Balko JM, Johnson DB, Zimmerman LJ, Liebler DC
(2017) Mol Cell Proteomics 16: 1705-1717
MeSH Terms: Acetylglucosamine, Adult, Aged, B7-H1 Antigen, Biopsy, Cohort Studies, Female, Glycosylation, Humans, Male, Mannose, Mass Spectrometry, Melanoma, Middle Aged, Polysaccharides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Protein Processing, Post-Translational, Skin Neoplasms, T-Lymphocytes
Show Abstract · Added March 14, 2018
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted MS platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from ∼0.03 to 1.5 fmol/microgram protein and the parallel reaction monitoring (PRM) data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody. PD-1 was measured at levels up to 20-fold lower than PD-L1, but the abundances were not significantly correlated (r = 0.062, = 0.264). PD-1 abundance was weakly correlated (r = 0.3057, = 0.009) with the fraction of lymphocytes and histiocytes in sections. PD-L2 was measured from 0.03 to 1.90 fmol/microgram protein and the ratio of PD-L2 to PD-L1 abundance ranged from 0.03 to 2.58. In 10 samples, PD-L2 was present at more than half the level of PD-L1, which suggests that PD-L2, a higher affinity PD-1 ligand, is sufficiently abundant to contribute to T-cell downregulation. We also identified five branched mannose and N-acetylglucosamine glycans at PD-L1 position N192 in all 22 samples. Extent of PD-L1 glycan modification varied by ∼10-fold and the melanoma with the highest PD-L1 protein abundance and most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function. Additional PRM analyses quantified immune checkpoint/co-regulator proteins LAG3, IDO1, TIM-3, VISTA, and CD40, which all displayed distinct expression independent of PD-1, PD-L1, and PD-L2. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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20 MeSH Terms
Myocarditis with Immune Checkpoint Blockade.
Moslehi JJ, Johnson DB, Sosman JA
(2017) N Engl J Med 376: 292
MeSH Terms: B7-H1 Antigen, Humans, Myocarditis, Programmed Cell Death 1 Receptor
Added March 26, 2017
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1 Members
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4 MeSH Terms
PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses.
Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A
(2017) Clin Cancer Res 23: 3371-3384
MeSH Terms: Aminopyridines, Animals, Cell Line, Tumor, Cell Proliferation, Class Ib Phosphatidylinositol 3-Kinase, Female, Humans, Immunity, Cellular, Mammary Neoplasms, Animal, Mice, Morpholines, Neoplasm Metastasis, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added January 4, 2017
Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity. The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or -null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and versus mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice. Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of in the host. The antitumor effect of loss in host, but not tumor, was partially reversed by CD8 T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone. PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. .
©2016 American Association for Cancer Research.
2 Communities
4 Members
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17 MeSH Terms
Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.
Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, Ali SM, Balasubramanian S, Sun JX, He Y, Frederick DT, Puzanov I, Balko JM, Cates JM, Ross JS, Sanders C, Robins H, Shyr Y, Miller VA, Stephens PJ, Sullivan RJ, Sosman JA, Lovly CM
(2016) Cancer Immunol Res 4: 959-967
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, B7-H1 Antigen, Biomarkers, Tumor, DNA Mutational Analysis, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Prognosis, Programmed Cell Death 1 Receptor, T-Lymphocytes, Transcriptome
Show Abstract · Added April 6, 2017
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. ©2016 AACR.
©2016 American Association for Cancer Research.
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3 Members
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21 MeSH Terms
Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy.
Greenplate AR, Johnson DB, Roussel M, Savona MR, Sosman JA, Puzanov I, Ferrell PB, Irish JM
(2016) Cancer Immunol Res 4: 474-480
MeSH Terms: Aged, Anemia, Refractory, with Excess of Blasts, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Disease Progression, Female, Flow Cytometry, Follow-Up Studies, Humans, Immunophenotyping, Melanoma, Myelodysplastic Syndromes, Programmed Cell Death 1 Receptor
Show Abstract · Added March 12, 2016
Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. ©2016 AACR.
©2016 American Association for Cancer Research.
4 Communities
2 Members
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13 MeSH Terms
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Johnson DB, Estrada MV, Salgado R, Sanchez V, Doxie DB, Opalenik SR, Vilgelm AE, Feld E, Johnson AS, Greenplate AR, Sanders ME, Lovly CM, Frederick DT, Kelley MC, Richmond A, Irish JM, Shyr Y, Sullivan RJ, Puzanov I, Sosman JA, Balko JM
(2016) Nat Commun 7: 10582
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Genes, MHC Class II, Genotype, Humans, Melanoma, Nivolumab, Programmed Cell Death 1 Receptor, RNA, Messenger
Show Abstract · Added January 30, 2016
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
4 Communities
6 Members
0 Resources
11 MeSH Terms
RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors.
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL, Giltnane JM, Estrada MV, Sánchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA, Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gómez H, Ryzhov SV, Darcy PK, Arteaga CL, Balko JM
(2016) Clin Cancer Res 22: 1499-509
MeSH Terms: Animals, B7-H1 Antigen, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Gene Expression Profiling, Humans, Immunomodulation, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Mice, Mitogen-Activated Protein Kinases, Mortality, Phenotype, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Transcriptome, Triple Negative Breast Neoplasms, ras Proteins
Show Abstract · Added April 6, 2017
PURPOSE - Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.
EXPERIMENTAL DESIGN - We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer.
RESULTS - Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras-MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.
CONCLUSIONS - These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
©2015 American Association for Cancer Research.
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2 Members
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22 MeSH Terms
Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion-like Phenotype.
Erickson JJ, Lu P, Wen S, Hastings AK, Gilchuk P, Joyce S, Shyr Y, Williams JV
(2015) J Immunol 195: 4319-30
MeSH Terms: Acute Disease, Animals, CD8-Positive T-Lymphocytes, Cluster Analysis, Gene Expression Profiling, Host-Pathogen Interactions, Humans, Lung, Metapneumovirus, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Paramyxoviridae Infections, Phenotype, Programmed Cell Death 1 Receptor, Respiratory Tract Infections, Spleen, Transcriptome
Show Abstract · Added October 2, 2015
Acute viral infections typically generate functional effector CD8(+) T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection, lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to Ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral lower respiratory infection, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections are unknown. In this study, we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during human metapneumovirus infection to those in acute or chronic lymphocytic choriomeningitis virus infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than do functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral Ag-induced TCR signaling is also required. Our results indicate that viral Ag in infected lungs rapidly induces an exhaustion-like state in lung TCD8 characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.
Copyright © 2015 by The American Association of Immunologists, Inc.
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19 MeSH Terms