NOL7 facilitates melanoma progression and metastasis

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

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The role of FoxP3+ regulatory T cells and IDO+ immune and tumor cells in malignant melanoma – an immunohistochemical study

BMC Cancer ◽

10.1186/s12885-021-08385-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Satu Salmi ◽

Anton Lin ◽

Benjamin Hirschovits-Gerz ◽

Mari Valkonen ◽

Niina Aaltonen ◽

...

Keyword(s):

T Cells ◽

Prognostic Factors ◽

Regulatory T Cells ◽

Tumor Cells ◽

Immune Cells ◽

Positive Association ◽

Tumor Stage ◽

Melanoma Cells ◽

Melanoma Progression

Abstract Background FoxP3+ Regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) participate in the formation of an immunosuppressive tumor microenvironment (TME) in malignant cutaneous melanoma (CM). Recent studies have reported that IDO expression correlates with poor prognosis and greater Breslow’s depth, but results concerning the role of FoxP3+ Tregs in CM have been controversial. Furthermore, the correlation between IDO and Tregs has not been substantially studied in CM, although IDO is known to be an important regulator of Tregs activity. Methods We investigated the associations of FoxP3+ Tregs, IDO+ tumor cells and IDO+ stromal immune cells with tumor stage, prognostic factors and survival in CM. FoxP3 and IDO were immunohistochemically stained from 29 benign and 29 dysplastic nevi, 18 in situ -melanomas, 48 superficial and 62 deep melanomas and 67 lymph node metastases (LNMs) of CM. The number of FoxP3+ Tregs and IDO+ stromal immune cells, and the coverage and intensity of IDO+ tumor cells were analysed. Results The number of FoxP3+ Tregs and IDO+ stromal immune cells were significantly higher in malignant melanomas compared with benign lesions. The increased expression of IDO in melanoma cells was associated with poor prognostic factors, such as recurrence, nodular growth pattern and increased mitotic count. Furthermore, the expression of IDO in melanoma cells was associated with reduced recurrence˗free survival. We further showed that there was a positive correlation between IDO+ tumor cells and FoxP3+ Tregs. Conclusions These results indicate that IDO is strongly involved in melanoma progression. FoxP3+ Tregs also seems to contribute to the immunosuppressive TME in CM, but their significance in melanoma progression remains unclear. The positive association of FoxP3+ Tregs with IDO+ melanoma cells, but not with IDO+ stromal immune cells, indicates a complex interaction between IDO and Tregs in CM, which demands further studies.

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588 Essential role of periostin in inflammation-associated melanoma progression in human and mouse

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.07.785 ◽

2017 ◽

Vol 137 (10) ◽

pp. S293

Author(s):

F. Ohno ◽

T. Nakahara ◽

M. Nakahara ◽

S. Nunomura ◽

K. Izuhara ◽

...

Keyword(s):

Essential Role ◽

Melanoma Progression ◽

Human And Mouse

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ROLE OF NUCLEAR FACTOR κB IN MELANOMA PROGRESSION.

Journal of Investigative Medicine ◽

10.1097/00042871-200701010-00513 ◽

2007 ◽

Vol 55 (1) ◽

pp. S158

Author(s):

A. M. DeLuca ◽

B. Ryu ◽

R. Alani

Keyword(s):

Nuclear Factor Κb ◽

Nuclear Factor ◽

Melanoma Progression

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773 Chronic inflammation promotes melanoma progression through modulating the tumor microenvironment - Emerging role of periostin

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.02.798 ◽

2017 ◽

Vol 137 (5) ◽

pp. S133

Author(s):

F. Ohno

Keyword(s):

Tumor Microenvironment ◽

Chronic Inflammation ◽

Melanoma Progression

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Potential role of CCL27 and CCR10 expression in melanoma progression and immune escape

European Journal of Cancer ◽

10.1016/j.ejca.2006.01.043 ◽

2006 ◽

Vol 42 (8) ◽

pp. 1181-1187 ◽

Cited By ~ 58

Author(s):

Oriana Simonetti ◽

Gaia Goteri ◽

Guendalina Lucarini ◽

Alessandra Filosa ◽

Tiziana Pieramici ◽

...

Keyword(s):

Potential Role ◽

Immune Escape ◽

Melanoma Progression ◽

Ccr10 Expression

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Exome sequencing in primary melanoma identifies novel drivers of melanoma progression

Journal of Translational Medicine ◽

10.1186/1479-5876-13-s1-p2 ◽

2015 ◽

Vol 13 (Suppl 1) ◽

pp. P2

Author(s):

Valentina Montagnani ◽

Matteo Benelli ◽

Alessandro Apollo ◽

Silvia Pandolfi ◽

Gianni Gerlini ◽

...

Keyword(s):

Exome Sequencing ◽

Primary Melanoma ◽

Melanoma Progression

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Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations

Cancers ◽

10.3390/cancers13092284 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2284

Author(s):

Serena Stamatakos ◽

Giovanni Luca Beretta ◽

Elisabetta Vergani ◽

Matteo Dugo ◽

Cristina Corno ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Mutant Cell ◽

Braf Inhibitor ◽

Cancer Cell Line ◽

Melanoma Cells ◽

Melanoma Progression ◽

Increased Sensitivity ◽

Resistant Cells

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

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