Deciphering Treg accumulation in melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22170-e22170
Author(s):  
Kristen E. Tobin Vealey ◽  
I. Caroline Le Poole ◽  
Jared S. Klarquist ◽  
Jonathan M. Eby
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Intervention Strategy ◽  
Host Immune System ◽  
Healthy Controls ◽  
Receptor Signaling ◽  
Melanoma Tumor ◽  
Melanoma Patients

e22170 Background: A high density of regulatory T-cells (Tregs) at melanoma tumor sites correlates with poor prognosis due to immunosuppressive effects on the host immune system. While the concentration of circulating Tregs in patients with melanoma is not significantly different from that of healthy controls, Tregs tend to accumulate at tumor sites. We hypothesized that the influx of Tregs observed in melanoma tumors may be explained by enhanced tumor homing. Methods: To quantify the relative expression of chemokine receptors CCL4 and CCL8, and skin homing receptor CLA, blood was drawn from five metastatic melanoma patients and five healthy controls. Lymphocytes were ficolled and negatively sorted for CD3 expression. T-cells were subjected to 7-color FACS staining where Tregs were defined as CD4+CD25+CD127lowFoxP3+ and were simultaneously assessed for expression of CCR4, CCR8, and CLA. To further understand chemokine-receptor signaling involved in Treg homing in melanoma we analyzed the number of CCL22 producing cells in four human metastatic melanoma tissues and four healthy skin tissues obtained during surgery. Dermal CCL22+ cells were detected by indirect immunohistochemistry and quantified to a depth of three times the thickness of the epidermis. Results: Lymphocytes of melanoma patients were found to exhibit enhanced expression of CCR4 (mean of 65.9 versus 51.2%, p<0.01) and CCR8 (3.0 versus 1.5%, p<0.05), but not CLA (21.9 versus 23.9%) as compared with healthy controls. The mean fluorescence intensities of CCR4 and CCR8 were likewise elevated by 63 and 49% over controls (p<0.05 and p<0.01), respectively. A markedly increased number of CCL22 secreting cells were found in tumor samples (mean of 1063.1 versus 207.4, p= 0.02) as compared with healthy controls. Conclusions: These data strongly suggest that enhanced homing of CCR4+ Tregs towards the ligand CCL22 is likely involved in accumulating Tregs at melanoma tumor sites, ultimately impeding effective anti-tumor immune responses. Targeting chemokine-receptor signaling may thus be an effective intervention strategy in melanoma.

scholarly journals A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Gregory Swan ◽  
Jia Geng ◽  
Eunchong Park ◽  
Quanquan Ding ◽  
John Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Cell Function ◽  
Critical Role ◽  
Immune Surveillance ◽  
Small Gtpases ◽  
Receptor Signaling ◽  
Lymphocyte Migration

Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.

CXC Chemokine Receptor 3 Expression by Activated CD8+ T cells Is Associated with Survival in Melanoma Patients with Stage III Disease

2004 ◽  
Vol 64 (21) ◽  
pp. 7697-7701 ◽  
Author(s):  
Irene M. Mullins ◽  
Craig L. Slingluff ◽  
Jae K. Lee ◽  
Courtney F. Garbee ◽  
Jianfen Shu ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Stage Iii ◽  
Cxc Chemokine ◽  
Melanoma Patients

scholarly journals Enrichment of melanoma-associated T cells in 6-thioguanine-resistant T cells from metastatic melanoma patients

2020 ◽  
Vol 30 (1) ◽  
pp. 52-61
Author(s):  
Cindy L. Zuleger ◽  
Michael A. Newton ◽  
Xiuyu Ma ◽  
Irene M. Ong ◽  
Qinglin Pei ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Melanoma Patients

scholarly journals Bim and PD-1 identify effector CD8 T cells responsive to anti-PD-1 therapy in metastatic melanoma patients

2015 ◽  
Vol 3 (S2) ◽  
Author(s):  
Roxana Dronca ◽  
Xin Liu ◽  
Kottschade Lisa ◽  
Rob Mcwilliams ◽  
Svetomir Markovic ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Melanoma Patients

scholarly journals NKG2D Polymorphism in Melanoma Patients from Southeastern Spain

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 438 ◽  
Author(s):  
Lourdes Gimeno ◽  
Helios Martínez-Banaclocha ◽  
M. Bernardo ◽  
José Bolarin ◽  
Luis Marín ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Southeastern Spain ◽  
Melanoma Patients ◽  
Risk Of Cancer

Background: Natural killer (NK) and CD8+ T cells are involved in the immune response against melanoma. C-Type lectin-like NK cell receptors are located in the Natural Killer Complex (NKC) region 12p13.2-p12.3 and play a critical role in regulating the activity of NK and CD8+ T cells. An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described. The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain. Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5′ Nuclease Assay in 233 melanoma patients and 200 matched healthy controls. Results: A linkage disequilibrium analysis of the SNPs performed in the NKC region revealed two blocks of haplotypes (Hb-1 and Hb-2) with 14 and seven different haplotype subtypes, respectively. The third most frequent haplotype from the block Hb-2—NK3 (CAT haplotype)—was significantly more frequent on melanoma patients than on healthy controls (p = 0.00009, Pc = 0.0006). No further associations were found when NKC SNPs were considered independently. Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma.

Analysis of regulatory T cells in patients of NSCLC with malignant pleural effusion.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17511-e17511
Author(s):  
Prabhat Singh Malik ◽  
Vinod Raina ◽  
Amar Singh ◽  
Dipendrea Kumar Mitra
Keyword(s):  
T Cells ◽  
Pleural Effusion ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Malignant Pleural Effusion ◽  
Advanced Nsclc ◽  
Treg Cells ◽  
Healthy Controls ◽  
Anatomic Site ◽  
Treg Frequency

e17511 Background: Enrichment of regulatory T (Treg) cells at the affected anatomic site in cancer may suppress the anti-tumor immune response influencing the cancer progression. Understanding of the clinical relevance of Treg mediated suppression of anti-tumor immune response and mechanisms underlying their preferential trafficking to the affected anatomic site is still limited. The aim of this study was to enumerate the frequencies of Treg cells in malignant pleural effusion and peripheral blood of patients with advanced NSCLC and it’s trend after treatment. Methods: Treg frequencies were evaluated in pleural effusion and peripheral blood of the patients with advanced NSCLC (n=27) using flowcytometry and compared with peripheral blood of age and sex matched healthy controls (n=15) and tubercular pleural effusions (n=10). The Treg cells were characterized as CD4+CD25+Foxp3+ T cells gated on CD4+CD25+ T cells. We assessed the effect of treatment response on Treg frequency. We have also looked for the expression of chemokine receptors CCR4 and CCR6 on the Tregs in pleural effusion and peripheral blood of the patients. Results: Compared to healthy controls, frequency of CD4+CD25+Foxp3+ Tregs was significantly increased in peripheral blood of patients with NSCLC (p=0.0036). In pleural effusion of patients, Treg frequency was higher than their corresponding peripheral blood (p=0.025). As compared to tubercular pleural effusion Treg frequency was higher in malignant effusion (p<0.0001). We had 12 patients who completed treatment and in whom response evaluation was available. Treg frequency reduced at the time of response (PR or SD) and increased again at disease progression. Surface expression of CCR4 and CCR6 was higher on Treg cells as compared to non Treg CD4 cells among the patients (p=0.0001; p=0.001 respectively). However, there was no difference in expression of these chemokine receptors on Tregs in pleural fluid and peripheral blood. Conclusions: Tregs are increased in patients of NSCLC, both at disease site and in systemic circulation. This increase may be chemokine receptors mediated. Treg frequency changes with treatment and response. Modulation of Tregs may have therapeutic implication in the management of advanced NSCLC.

scholarly journals LMD-20. Immune Suppressive Macrophages and Signal Transducer and Activator of Transcription 3 (STAT3) Expression are common in Melanoma Leptomeningeal Disease

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii11-iii12
Author(s):  
Hinda Najem ◽  
Anantha Marisetty ◽  
Craig Horbinski ◽  
Jared Burks ◽  
Amy B Heimberger
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Stage Iv ◽  
Tumor Stroma ◽  
Leptomeningeal Disease ◽  
Signal Transducer ◽  
Melanoma Tumor ◽  
Immune Cell Population ◽  
Melanoma Patients ◽  
Transcription 3

Abstract Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological impairments and has a dismal outcome with a median survival of 1.8 months. Despite the therapeutic benefit of targeted therapies and immunotherapies for most kinds of Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3 T cells, CD68+ monocytes, CD163 immune suppressive macrophages, CD11c+ antigen presenting cells (APCs) in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD163+ macrophage is the most frequent immune cell population in the LMD TME. Occasional CD3+ T cells and CD11c+ APC are also identified, although the latter has concurrent expression of CD163. STAT3 nuclear localization is heterogeneously expressed in the various immune cell populations. Occasional immune cluster interactions can be seen in the tumor stroma and the tumor edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells, but is enriched for immune suppression and innate immunity.

scholarly journals Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies

2020 ◽  
Vol 8 (1) ◽  
pp. e000368
Author(s):  
Jason Cham ◽  
Li Zhang ◽  
Serena Kwek ◽  
Alan Paciorek ◽  
Tao He ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Flow Cytometry Analysis ◽  
Cell Repertoire ◽  
Gm Csf ◽  
Cell Counts ◽  
Melanoma Patients ◽  
Circulating T Cells

BackgroundCTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.MethodsWe used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman’s rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.ResultsWhile melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=−0.81, p<0.001 vs r=−0.59, p=0.02).Trial registration numbersNCT00064129;NCT01363206.

scholarly journals A Full GMP Process to Select and Amplify Epitope-Specific T Lymphocytes for Adoptive Immunotherapy of Metastatic Melanoma

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
N. Labarriere ◽  
A. Fortun ◽  
A. Bellec ◽  
A. Khammari ◽  
B. Dreno ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Metastatic Melanoma ◽  
Clinical Setting ◽  
Magnetic Beads ◽  
Clinical Grade ◽  
Melanoma Antigens ◽  
Peptide Complexes ◽  
Melanoma Patients ◽  
Peptide Stimulation

A number of trials of adoptive transfer of tumor-specific T lymphocytes have been performed in the last 20 years in metastatic melanoma, with increasingly encouraging results as the relevant melanoma antigens were identified and the purity/specificity of injected T cells improved. We have previously described a sorting method of epitope-specific T lymphocytes that uses magnetic beads coated with HLA/peptide complexes and we suggested that this method could be applied to a clinical setting. In the present work, we provide a detailed description of the whole GMP process of sorting and amplification of clinical grade T cells specific for the melanoma antigens Melan-A and MELOE-1. All the reagents used in this process including the sorting reagent were produced in GMP conditions and we document the optimization of the different steps of the process such as peptide stimulation, sorting, and amplification. The optimized procedure, validated in 3 blank runs in a clinical setting, allowed the production of at least 108pure (>90%) Melan-A- and MELOE-1-specific T cells within 28 days starting with 100 mL of blood from metastatic melanoma patients. This GMP process is thus ready to be used in an upcoming phase I/II clinical trial on metastatic melanoma patients.

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