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Results: 11 to 16 of 16

Publication Record


Connecting the Dots: Therapy-Induced Senescence and a Tumor-Suppressive Immune Microenvironment.
Vilgelm AE, Johnson CA, Prasad N, Yang J, Chen SC, Ayers GD, Pawlikowski JS, Raman D, Sosman JA, Kelley M, Ecsedy JA, Shyr Y, Levy SE, Richmond A
(2016) J Natl Cancer Inst 108: djv406
MeSH Terms: Animals, Aurora Kinase A, Cell Line, Tumor, Cellular Senescence, Chemokine CCL5, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Immunocompetence, Immunocompromised Host, Immunotherapy, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Melanoma, Mice, Real-Time Polymerase Chain Reaction, Skin Neoplasms, Transcriptome, Tumor Microenvironment, Tumor Necrosis Factor Receptor Superfamily, Member 9
Show Abstract · Added January 18, 2016
BACKGROUND - Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of immunotherapy in melanoma.
METHODS - Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided.
RESULTS - AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P < .001). AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner. Therapeutic response to AURKAi was impaired in immunodeficient compared with immunocompetent mice (0% vs 67% tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P < .001). In human tumors, CCL5 expression was also induced by AURKAi (P ≤ .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93).
CONCLUSIONS - Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
2 Communities
3 Members
0 Resources
25 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.
1 Communities
2 Members
0 Resources
22 MeSH Terms
B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression.
Irish JM, Myklebust JH, Alizadeh AA, Houot R, Sharman JP, Czerwinski DK, Nolan GP, Levy R
(2010) Proc Natl Acad Sci U S A 107: 12747-54
MeSH Terms: B-Lymphocytes, CD40 Antigens, Disease Progression, Enzyme Activation, Extracellular Space, Humans, Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, Lymphoma, Follicular, Models, Immunological, Phenotype, Phosphoprotein Phosphatases, Prognosis, Receptors, Antigen, B-Cell, Reproducibility of Results, Signal Transduction, Survival Analysis
Show Abstract · Added February 15, 2013
Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient's disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell-cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells.
Irish JM, Czerwinski DK, Nolan GP, Levy R
(2006) Blood 108: 3135-42
MeSH Terms: B-Lymphocytes, Humans, Lymphocytes, Tumor-Infiltrating, Lymphoma, B-Cell, Lymphoma, Follicular, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added February 15, 2013
The B-cell receptor (BCR) transmits life and death signals throughout B-cell development, and altered BCR signaling may be required for survival of B-lymphoma cells. We used single-cell signaling profiles to compare follicular lymphoma (FL) B cells and nonmalignant host B cells within individual patient biopsies and identified BCR-mediated signaling events specific to lymphoma B cells. Expression of CD20, Bcl-2, and BCR light chain isotype (kappa or lambda) distinguished FL tumor B-cell and nontumor host B-cell subsets within FL patient biopsies. BCR-mediated signaling via phosphorylation of Btk, Syk, Erk1/2, and p38 occurred more rapidly in tumor B cells from FL samples than in infiltrating nontumor B cells, achieved greater levels of per-cell signaling, and sustained this level of signaling for hours longer than nontumor B cells. The timing and magnitude of BCR-mediated signaling in nontumor B cells within an FL sample instead resembled that observed in mature B cells from the peripheral blood of healthy subjects. BCR signaling pathways that are potentiated specifically in lymphoma cells should provide new targets for therapeutic attention.
1 Communities
1 Members
0 Resources
7 MeSH Terms
Mechanisms of apoptosis in T cells from patients with renal cell carcinoma.
Uzzo RG, Rayman P, Kolenko V, Clark PE, Bloom T, Ward AM, Molto L, Tannenbaum C, Worford LJ, Bukowski R, Tubbs R, Hsi ED, Bander NH, Novick AC, Finke JH
(1999) Clin Cancer Res 5: 1219-29
MeSH Terms: Apoptosis, Blood Cells, Carcinoma, Renal Cell, DNA Fragmentation, Fas Ligand Protein, Humans, In Situ Nick-End Labeling, Ionomycin, Jurkat Cells, Kidney Neoplasms, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Membrane Glycoproteins, Muromonab-CD3, Neoplasm Proteins, Polymerase Chain Reaction, RNA, Messenger, RNA, Neoplasm, T-Lymphocytes, Cytotoxic, Tetradecanoylphorbol Acetate, Tumor Cells, Cultured, fas Receptor
Show Abstract · Added May 27, 2014
Tumors may escape immune recognition and destruction through the induction of apoptosis in activated T lymphocytes. Results from several laboratories suggest that FasL (L/CD95L) expression in tumors may be responsible for this process. In this study of patients with renal cell carcinoma (RCC), we provide evidence for two mechanisms of T-cell apoptosis. One mechanism involves the induction of apoptosis via FasL expression in tumor cells. This is supported by several observations, including the fact that tumor cells in situ as well as cultured cell lines expressed FasL mRNA and protein by a variety of techniques. The FasL in RCC is functional because in coculture experiments, FasL+ tumors induced apoptosis in Fas-sensitive Jurkat T cells and in activated peripheral blood T cells but not in resting peripheral blood T cells. Most importantly, antibody to FasL partially blocked apoptosis of the activated T cells. Moreover, Fas was expressed by T cells derived from the peripheral blood (53% median) and tumor (44.3% median) of RCC patients. Finally, in situ staining for DNA breaks demonstrated apoptosis in a subset of T cells infiltrating renal tumors. These studies also identified a second mechanism of apoptosis in RCC patient peripheral T cells. Whereas these cells did not display DNA breaks when freshly isolated or after culture for 24 h in medium, peripheral blood T cells from RCC patients underwent activation-induced cell death after stimulation with either phorbol 12-myristate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by exposure to FasL in tumor cells or through T-cell activation may contribute to the failure of RCC patients to develop an effective T-cell-mediated antitumor response.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Cytokines and immunological monitoring.
Sosman JA, Sawhaney A
(1997) Cancer Chemother Biol Response Modif 17: 217-86
MeSH Terms: Animals, Cytokines, Granulocyte Colony-Stimulating Factor, Humans, Immunotherapy, Adoptive, Interferons, Interleukin-1, Interleukin-2, Interleukin-3, Lymphocytes, Tumor-Infiltrating, Neoplasms, Tumor Necrosis Factor-alpha
Added March 5, 2014
0 Communities
1 Members
0 Resources
12 MeSH Terms