Aqueous Humor Biomarkers Identify Three Prognostic Groups in Uveal Melanoma.
Invest Ophthalmol Vis Sci. 2019 Nov 01;60(14):4740-4747
Authors: Wierenga APA, Cao J, Mouthaan H, van Weeghel C, Verdijk RM, van Duinen SG, Kroes WGM, Dogrusöz M, Marinkovic M, van der Burg SSH, Luyten GPM, Jager MJ
Purpose: To investigate whether we can identify different patterns of inflammation in the aqueous humor of a uveal melanoma (UM)-containing eye, and whether these are related to prognosis.
Methods: Ninety samples of aqueous humor from UM-containing eyes were analyzed using a high-throughput multiplex immunoassay that enables simultaneous analysis of 92 predefined protein biomarkers. Cytokine expression was compared to clinical and histopathological characteristics. Cluster analysis was performed, after which the clusters were compared with clinical and histopathological tumor characteristics.
Results: Cluster analysis revealed three distinct clusters, with one cluster showing hardly any inflammatory cytokines, one showing intermediate levels, and one showing a high expression of inflammation-related biomarkers. Significant differences between the clusters were seen with regard to patient age (P = 0.008), tumor prominence (P = 0.001), ciliary body involvement (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P < 0.001), monosomy of chromosome 3 (P = 0.03), and gain of chromosome 8q (P = 0.04), with the cluster with a highest cytokine expression having the worst prognostic markers. Especially apoptosis-related cytokines were differentially expressed.
Conclusions: Analysis of cytokines in the aqueous humor shows distinct differences between aqueous humor samples and allocates these samples into three different prognostic tumor clusters. Especially large tumors with ciliary body involvement and monosomy 3 were associated with many cytokines, especially apoptosis-related cytokines. The presence of these cytokines in the aqueous humor may play a role in the lack of effective antitumor immune responses.
PMID: 31731294 [PubMed - in process]
Desmoplastic neurotropic melanoma of the buccal sulcus invading the inferior alveolar nerve subjected to interstitial photodynamic therapy.
Photodiagnosis Photodyn Ther. 2019 Nov 12;:101601
Authors: Jerjes W, Hamdoon Z, Hopper C
PMID: 31731065 [PubMed - as supplied by publisher]
The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors.
J Immunother Cancer. 2019 Nov 15;7(1):308
Authors: Massi D, Rulli E, Cossa M, Valeri B, Rodolfo M, Merelli B, De Logu F, Nassini R, Del Vecchio M, Di Guardo L, De Penni R, Guida M, Sileni VC, Di Giacomo AM, Tucci M, Occelli M, Portelli F, Vallacchi V, Consoli F, Quaglino P, Queirolo P, Baroni G, Carnevale-Schianca F, Cattaneo L, Minisini A, Palmieri G, Rivoltini L, Mandalà M, Italian Melanoma Intergroup
BACKGROUND: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors.
METHODS: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received.
RESULTS: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068).
CONCLUSIONS: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.
PMID: 31730502 [PubMed - in process]
Synthesis and Characterization of Ru(II) Complexes with π-Expansive Imidazophen Ligands for the Photokilling of Human Melanoma Cells.
Photochem Photobiol. 2019 Nov 15;:
Authors: Ghosh G, Yin H, Monro SMA, Sainuddin T, Lapoot L, Greer A, McFarland SA
Ru(II) complexes were synthesized with π-expanding (phenyl, fluorenyl, phenanthrenyl, naphthalen-1-yl, naphthalene-2-yl, anthryl, and pyrenyl groups) attached at a 1H-imidazo[4,5-f][1,10]phenanthroline ligand and 4,4'-dimethyl-2,2'-bipyridine (4,4'-dmb) co-ligands. These Ru(II) complexes were characterized by 1D and 2D NMR, and mass spectroscopy, and studied for visible-light and dark toxicity to human malignant melanoma SK-MEL-28 cells. In the SK-MEL-28 cells, the Ru(II) complexes are highly phototoxic (EC50 = 0.2-0.5 µM), and have low dark toxicity (EC50 = 58-230 µM). The highest phototherapeutic index (PI) of the series was found with the Ru(II) complex bearing the 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline ligand. This high PI is in part attributed to the π-rich character added by the pyrenyl group, and a possible low-lying and longer-lived 3 IL state due to equilibration with the 3 MLCT state. While this pyrenyl Ru(II) complex possessed a relatively high quantum yield for singlet oxygen formation (Φ∆ = 0.84), contributions from type-I processes (oxygen radicals and radical ions) are competitive with the type-II (1 O2 ) process based on effects of added sodium azide and solvent deuteration.
PMID: 31730278 [PubMed - as supplied by publisher]
ER-aminopeptidase 1 determines the processing and presentation of an immunotherapy-relevant melanoma epitope.
Eur J Immunol. 2019 Nov 15;:
Authors: Textoris-Taube K, Cammann C, Henklein P, Topfstedt E, Ebstein F, Henze S, Liepe J, Zhao F, Schadendorf D, Dahlmann B, Uckert W, Paschen A, Mishto M, Seifert U
Dissecting the different steps of the processing and presentation of tumor-associated antigens is a key aspect of immunotherapies enabling to tackle the immune response evasion attempts of cancer cells. The immunodominant glycoprotein gp100209-217 epitope, which is liberated from the melanoma differentiation antigen gp100PMEL17 , is part of immunotherapy trials. By analyzing different human melanoma cell lines, we here demonstrate that a pool of N-terminal extended peptides sharing the common minimal epitope is generated by melanoma proteasome subtypes. In vitro and in cellulo experiments indicate that ER-resident aminopeptidase 1 (ERAP1) - but not ERAP2 - defines the processing of this peptide pool thereby modulating the T cell recognition of melanoma cells. By combining the outcomes of our studies and others, we can sketch the complex processing and endogenous presentation pathway of the gp100209-217 -containing epitope/peptides, which are produced by proteasomes and are translocated to the vesicular compartment through different pathways, where the precursor peptides that reach the endoplasmic reticulum are further processed by ERAP1. The latter step enhances the activation of epitope-specific T lymphocytes, which might be a target to improve the efficiency of anti-melanoma immunotherapy. This article is protected by copyright. All rights reserved.
PMID: 31729751 [PubMed - as supplied by publisher]