Phase- and Stage-Related Proportions of T Cells Bearing the Transcription Factor FOXP3 Infiltrate Primary Melanoma

Panfilis, Giuseppe De; Campanini, Nicoletta; Santini, Marcello; Mori, Giovanni; Tognetti, Elena; Maestri, Roberta; Lombardi, Mara; Froio, Elisabetta; Ferrari, Donata; Ricci, Roberto

doi:10.1038/sj.jid.5701046

Cited by 26 publications

(23 citation statements)

References 67 publications

(88 reference statements)

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“…We did not make attempts to characterize the labeled cell type(s) more precisely by double immunohistochemical staining. Although the expression of FOXP3 could be induced in vitro in CD4 + CD25 − and CD8 + lymphocytes as well [26][27][28][29], in previous immunohistochemical studies on melanoma all FOXP3 + cells expressed CD3 and almost all of them CD4 and CD25 as well [18,19], suggesting that the vast majority of tumor-infiltrating FOXP3 + cells are CD4 + CD25 + T lymphocytes.…”

Section: Discussionmentioning

confidence: 90%

“…Mourmouras et al characterized cutaneous melanocytic lesions including melanomas with respect to the prevalence of Tregs, and found a lower percentage of Tregs in vertical than in radial growth phase melanomas [18]. Contrary to this finding, another small-scale study described higher prevalence of these cells in VGP compared to RGP, and also in stage III-IV tumors compared to stage I ones [19]. Miracco et al, in a study performed on vertical growth phase melanomas, reported that high intra-and peritumoral percentage of Tregs predicted local recurrence [20].…”

Section: Introductionmentioning

confidence: 95%

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FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

Ladányi

Mohos

Somlai

et al. 2010

Pathol. Oncol. Res.

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Regulatory T cells (Tregs) have been implicated as inhibitors of antitumor immune reactions. However, data on the relevance of their prevalence at tumor sites in influencing disease outcome are controversial. The aim of our study was to investigate the role in tumor progression and the prognostic impact of the density of lymphocytes expressing FOXP3, a transcription factor expressed predominantly by CD4 + CD25 + Tregs, in primary cutaneous melanoma. We examined the infiltration of FOXP3 + cells by immunohistochemistry in tumor samples from 97 patients and evaluated in relation to patient and tumor parameters. The degree of infiltration by FOXP3 + cells did not show correlation with the thickness of melanomas. Moreover, no associations were found with metastasis formation during the 5-year follow-up period, patient survival, or any other clinicopathologic parameters studied. These results suggest that the presence of FOXP3 + lymphocytes in primary tumors is not of prognostic importance in human cutaneous melanoma.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 95%

FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

Ladányi

Mohos

Somlai

et al. 2010

Pathol. Oncol. Res.

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“…Immune-suppressive CD4 + FoxP3 + CD25 high Tregs accumulate in primary and metastatic melanomas, which undermines spontaneous and/or vaccine-induced immune responses against melanomas (12)(13)(14). The aim of this study was to investigate whether a single low dose of daclizumab (0.5 mg/kg) transiently depletes Tregs in melanoma patients and to assess possible effects of this drug on immunity following dendritic cell vaccinations.…”

Section: Discussionmentioning

confidence: 99%

“…In melanoma patients, selective accumulation of Tregs in the primary tumor, tumor-infiltrated lymph nodes, and in metastases has been observed (12)(13)(14). The functional importance of these Tregs is shown in mouse melanoma models in which transient Treg depletion induces antitumor immunity (15)(16)(17)(18)(19).…”

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confidence: 99%

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Jacobs

Punt

Lesterhuis

et al. 2010

Clinical Cancer Research

211

175

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Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25 high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.Experimental Design: Thirty HLA-A2.1 + metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.Results: Daclizumab efficiently depleted all CD25 high immune cells, including CD4 + FoxP3 + CD25 high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25 + cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25 + T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.Conclusions: Although daclizumab depleted the CD4 + FoxP3 + CD25 high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25 + effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067-78. ©2010 AACR.Melanoma is considered one of the most immunogenic types of cancers. This is based on the following arguments: (a) several melanoma-specific antigens have been identified (1, 2); (b) functional lymphocytes specific for melanoma antigens are increased in melanoma patients (3); (c) immune-stimulating agents can have a positive effect on disease outcome (4, 5); and (d) spontaneous melanoma regressions with simultaneous onset of vitiligo have been reported (6).Immunotherapeutic clinical trials have succeeded in expanding melanoma-specific effector T cells in vivo, but favorable outcomes are still limited because tumor-induced mechanisms of immune evasion may render the host tolerant for melanoma antigens (7,8). Immunosuppression at the tumor microenvironment mediated by regulatory T cells (Treg) is one of the most critical mechanisms of tumor-immune escape and a major hurdle for successful immunotherapy (9-11).In melanoma patients, selective...

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“…[29][30][31] Paraffin blocks were serially cut into 5 mm sections and serial sections from each specimen were routinely stained with hematoxylin-eosin for histological examination.…”

Section: Patient Treatment and Immunohistochemistrymentioning

confidence: 99%

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Gobbi

Ricci

Malinverno

et al. 2009

Laboratory Investigation

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The effects of exogenous hydrogen sulfide (H 2 S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H 2 S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H 2 S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of b4, a2 and a6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.

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Phase- and Stage-Related Proportions of T Cells Bearing the Transcription Factor FOXP3 Infiltrate Primary Melanoma

Cited by 26 publications

References 67 publications

FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

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