Uveal Melanoma: The Inflammatory Microenvironment

Bronkhorst, Inge H. G.; Jager, Martine J.

doi:10.1159/000334576

Cited by 82 publications

(70 citation statements)

References 97 publications

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“…Tregs may, thus, not be the main suppressor cells at the tumor site, whereas other suppressive cells may hamper antitumor immunity locally in our model. In line with such an assumption, we have recently shown that type 2 macrophages infiltrate massively the most aggressive metastases (21), which is consistent with observations in human melanoma biopsies (26)(27)(28). In contrast, the proportion of Tregs among CD4 + T cells was increased in the spleen and TdLNs of MT/ret mice without vitiligo, in agreement with the accumulation of Tregs observed in TdLNs few days after tumor cell implantation in several transplanted tumor models (7).…”

Section: Discussionsupporting

confidence: 90%

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Pommier

Audemard

Durand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4 + T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4 + T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.T he concept of suppressive T cells, which was first described in the early 1970s, remained poorly investigated until Sakaguchi et al. demonstrated the suppressive functions of a subset of CD4 + T cells now called regulatory T cells (Tregs) (1). Tregs express Foxp3 (2) and high surface levels of the α-chain of the IL-2 receptor (CD25) and are the main mediators of peripheral tolerance under physiological settings (1). Their role in the suppression of antitumor immunity was originally described in the 1980s (3) but remained, at first, largely underestimated. The demonstration that systemic depletion of Tregs favors tumor rejection in mouse models highlighted their contribution in tumor progression (4). Whereas it is established that Tregs potently interfere with tumorspecific T cells (5-8), their impact on innate immune cells, in particular, on myeloid cells, has been clearly less investigated in the context of tumor development (9, 10).To decipher the role of Tregs in the relationship between cancer immunity and autoimmunity, we used mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice) (11). In this model, the primary uveal tumor disseminates early but remains dormant for several weeks (12, 13). MT/ret mice then develop cutaneous metastases and finally distant (i.e., pulmonary, visceral, and mediastinal adenopathy) metastases (14). A significant proportion of MT/ret mice spontaneously develops vitiligo-like depigmentations. The tumor progression is significantly delayed in mice harboring vitiligo compared with mice without depigmented skin (14). The development of vitiligo in melanoma patients has...

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Section: Discussionsupporting

confidence: 90%

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Pommier

Audemard

Durand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Aberrations were observed in all chromosomes, with chromosomes 1, 3,6,8,13,15,16, and Y being altered in at least 15% of the tumors. Aberrations were more common and more complex in previously irradiated tumors (significant for chromosomes 5 [P ¼ 0.004] and 13 [P ¼ 0.04]).…”

Section: Methodsmentioning

confidence: 98%

Radiation Treatment Affects Chromosome Testing in Uveal Melanoma

Doğrusöz

Kroes

Duinen

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to determine whether radiation treatment induces chromosomal aberrations in uveal melanoma (UM) and to evaluate which tumor features determine success of karyotyping and FISH. METHODS.Material from 327 UM-containing enucleated eyes was submitted for karyotyping, while FISH for chromosome 3 was performed in 248 samples. Thirty-six UMs had previously undergone irradiation. Karyotypes were analyzed, and the success rate of karyotyping/FISH was evaluated and compared with clinicopathologic tumor characteristics and prior irradiation.RESULTS. Aberrations were observed in all chromosomes, with chromosomes 1, 3,6,8,13,15,16, and Y being altered in at least 15% of the tumors. Aberrations were more common and more complex in previously irradiated tumors (significant for chromosomes 5 [P ¼ 0.004] and 13 [P ¼ 0.04]). Karyotyping and FISH failed significantly more often in irradiated tumors (both P < 0.001). In nonirradiated cases, successful karyotyping was related to a large tumor prominence (P ¼ 0.004) and a high mitotic count (P ¼ 0.007). The success of FISH in these tumors was not associated with any of the studied parameters. In irradiated tumors, karyotyping succeeded more frequently in cases with a high mitotic count (P ¼ 0.03), whereas FISH was more often successful in tumors with a high mitotic count (P ¼ 0.001), a large diameter (P ¼ 0.009) and large prominence (P ¼ 0.008).CONCLUSIONS. Karyotyping and FISH are more often successful in UMs with features characteristic of high tumor aggressiveness, whereas prior irradiation leads to multiple chromosome aberrations and to unsuccessful tests. It will be interesting to determine whether other techniques can provide reliable information on the chromosome status of previously irradiated UMs.

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“…Tumourpromoting inflammation Lymphocytes Macrophages Dendritic cells Varying densities of tumour infiltrating lymphocytes and macrophages; both associated with worse prognoses [54][55][56][57][58][59] In the following paragraphs, the major molecular pathway defects and the most common chromosomal alterations in UM development will be summarised.…”

Section: Enabling Characteristics 1 Genome Instability and Mutationmentioning

confidence: 99%

Molecular Pathology of Uveal Melanoma

Coupland

Lake

Damato

2014

Clinical Ophthalmic Oncology

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Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. Characteristic chromosomal abnormalities are common and include 6p gain, associated with a good prognosis, as well as 1p loss, 3 loss, and 8q gain, which correlate with high mortality. These are identified by techniques such as fluorescence in situ hybridisation, comparative genomic hybridisation, microsatellite analysis, multiplex ligationdependent probe amplification, and singlenucleotide polymorphisms. UM can also be categorised by their gene expression profiles as class 1 or class 2, the latter correlating with poor survival, as do BRCA1-associated protein-1 (BAP1) inactivating mutations. Genetic testing of UM has enhanced prognostication, especially when results are integrated with histological and clinical data. The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life.

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Uveal Melanoma: The Inflammatory Microenvironment

Cited by 82 publications

References 97 publications

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Radiation Treatment Affects Chromosome Testing in Uveal Melanoma

Molecular Pathology of Uveal Melanoma

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Uveal Melanoma: The Inflammatory Microenvironment

Cited by 82 publications

References 97 publications

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

Radiation Treatment Affects Chromosome Testing in Uveal Melanoma

Molecular Pathology of Uveal Melanoma

Contact Info

Product

Resources

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Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4⁺T cells