Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Cancer Res ; 80(21): 4707-4719, 2020 11 01.
Article in English | MEDLINE | ID: mdl-33004350

ABSTRACT

T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T-cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults. SIGNIFICANCE: These findings demonstrate that manipulation of T-cell EZH2 in cellular therapies may yield cellular products able to withstand solid tumor metabolic-deficient environments. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4707/F1.large.jpg.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/metabolism , Enhancer of Zeste Homolog 2 Protein/metabolism , Lymphocytes, Tumor-Infiltrating/metabolism , Neoplasms, Experimental/immunology , Animals , Cell Line, Tumor , Epigenesis, Genetic/physiology , Mice , Tumor Microenvironment/immunology
2.
Cancer Res ; 79(6): 1113-1123, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30674537

ABSTRACT

Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1-/- and CD103-/- mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin-expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets.Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin-expressing malignancies.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/6/1113/F1.large.jpg.


Subject(s)
Antigens, CD/metabolism , Antineoplastic Agents, Immunological/pharmacology , Cadherins/metabolism , Cell Cycle Checkpoints/drug effects , Integrin alpha Chains/metabolism , Lung Neoplasms/secondary , Melanoma, Experimental/pathology , Animals , Antigens, CD/genetics , Apoptosis , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cadherins/antagonists & inhibitors , Cadherins/genetics , Cell Proliferation , Gene Expression Regulation, Neoplastic , Integrin alpha Chains/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Melanoma, Experimental/drug therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice , Tumor Cells, Cultured , Tumor Microenvironment
3.
J Oncol Pharm Pract ; 24(6): 468-472, 2018 Sep.
Article in English | MEDLINE | ID: mdl-28625074

ABSTRACT

The field of gut microbiota is of growing interest, especially in the recent discoveries of its interaction with host immune responses, which when disrupted, can further alter immunity. It also plays a role in cancer development, its microenvironment and response to anticancer therapeutics. Several recently published experimental studies had explored the efficacy of modifying microbiota to enhance the response of checkpoint inhibitors, suggesting its beneficial function in cancer management and potential to be targeted as a therapeutic agent to enhance efficacy of checkpoint inhibitors. Here we review available evidence, mechanisms and hypotheses of its use to enhance cancer response.


Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Microbiome , Neoplasms/drug therapy , Humans
4.
Cancer Biol Ther ; 18(7): 451-469, 2017 Jul 03.
Article in English | MEDLINE | ID: mdl-28513269

ABSTRACT

Pharmacologic inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death receptor-1 (PD1) has resulted in unprecedented durable responses in metastatic melanoma. However, resistance to immunotherapy remains a major challenge. Effective immune surveillance against melanoma requires 4 essential steps: activation of the T lymphocytes, homing of the activated T lymphocytes to the melanoma microenvironment, identification and episode of melanoma cells by activated T lymphocytes, and the sensitivity of melanoma cells to apoptosis. At each of these steps, there are multiple factors that may interfere with the immune surveillance machinery, thus allowing melanoma cells to escape immune attack and develop resistance to immunotherapy. We provide a comprehensive review of the complex immune surveillance mechanisms at play in melanoma, and a detailed discussion of how these mechanisms may allow for the development of intrinsic or acquired resistance to immunotherapeutic modalities, and potential avenues for overcoming this resistance.


Subject(s)
Immunologic Surveillance , Melanoma/immunology , Tumor Escape/immunology , Animals , Apoptosis/genetics , Apoptosis/immunology , Cell Movement , Humans , Immunomodulation , Immunotherapy , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Melanoma/metabolism , Melanoma/pathology , Melanoma/therapy , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
5.
Sci Rep ; 7(1): 807, 2017 04 11.
Article in English | MEDLINE | ID: mdl-28400597

ABSTRACT

Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to checkpoint blockade, which revealed biological signatures that can stratify patients as responders or non-responders. Furthermore, our findings provide evidence of mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Our results have implications for checkpoint inhibitor therapy as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness.


Subject(s)
Antibodies, Monoclonal/immunology , CTLA-4 Antigen/immunology , Drug Resistance, Neoplasm , Histone Code , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/immunology , Antibodies, Monoclonal/therapeutic use , CTLA-4 Antigen/antagonists & inhibitors , Epithelial-Mesenchymal Transition , Humans , Melanoma/genetics , Melanoma/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Proteome/metabolism , T-Lymphocytes/metabolism
6.
Cancer Biol Ther ; 17(6): 579-91, 2016 06 02.
Article in English | MEDLINE | ID: mdl-27105109

ABSTRACT

There is accumulating evidence that the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.


Subject(s)
Enhancer of Zeste Homolog 2 Protein/metabolism , Histones/metabolism , Melanoma/genetics , Disease Progression , Epigenomics , Humans , Neoplasm Metastasis
7.
Mol Cell Proteomics ; 15(3): 765-75, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26621846

ABSTRACT

Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys(27) trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications.


Subject(s)
Histones/metabolism , Lysine/metabolism , Mass Spectrometry/methods , Multiple Myeloma/metabolism , Up-Regulation , Cadherins/genetics , Cell Line, Tumor , Core Binding Factor Alpha 1 Subunit/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Humans , Methylation , Multiple Myeloma/genetics , Neoplasm Metastasis , Protein Processing, Post-Translational
8.
Glob Dermatol ; 3(4): 366-370, 2016 Aug.
Article in English | MEDLINE | ID: mdl-30214824

ABSTRACT

Proteomics is the study of the protein complement of the genome, and this powerful technique complements genomic studies. Proteomic experiments result in the generation of large volumes of data requiring complicated analysis algorithms and subsequent confirmatory studies. Until recently, technological limitations of experimental protocols precluded the use of formalin-fixed tissues for these types of studies. Recent advances have allowed the use of valuable archived patient tissue samples in proteomic research, resulting in an opportunity to perform cutting edge translational research. The field of melanoma research stands to benefit greatly from collaboration between dermatopathologists and proteomic scientists. This article seeks to: 1) describe proteomics for dermatologists and pathologists, including the tools used in proteomic research, and 2) convey a historical account of proteomic studies within the field of melanoma followed by a discussion on how recent advances are informing current studies.

9.
J Proteomics Bioinform ; 9(Suppl 10)2016.
Article in English | MEDLINE | ID: mdl-29910559

ABSTRACT

Proteomics is a relatively young discipline while pathology is one of the oldest forms of scientific inquiry. These two fields have different methods and aims, but have many areas of overlap and shared interests. Cultivation of synergistic projects between physicians who study static images of disease and biologists who study the dynamic environment that produces disease states will help further biomedical research providing new diagnostic, prognostic, and therapeutic approaches. Here, a pathologist and a proteomic scientist share their views on recent collaborations among the fields.

10.
Patient Relat Outcome Meas ; 6: 205-14, 2015.
Article in English | MEDLINE | ID: mdl-26251635

ABSTRACT

BACKGROUND: There is a need for a survey instrument to measure arthralgia (joint pain) that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI) to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia. METHODS: We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer) at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy. RESULTS: Cronbach's alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87-0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: -0.3, 95% confidence interval [CI] -0.5, -0.2; P<0.001). The PRAI was highly correlated with the Functional Assessment of Cancer Therapy-Endocrine Subscale item "I have pain in my joints" (reference instrument; Spearman r range: 0.76-0.82). Greater arthralgia severity on the PRAI was also related to decreased physical function (r=-0.47, 95% CI -0.55, -0.37; P<0.001), higher pain interference (r=0.65, 95% CI 0.57-0.72; P<0.001), less active performance status (estimated difference in location (-0.6, 95% CI -0.9, -0.4; P<0.001), and increased morning stiffness duration (r=0.62, 95% CI 0.54-0.69; P<0.0001). CONCLUSION: We conclude that the psychometric properties of the PRAI are satisfactory for measuring arthralgia severity.

SELECTION OF CITATIONS
SEARCH DETAIL
...