Melanoma Cell Adhesion Molecule Expressing Helper T Cells in CNS Inflammatory Demyelinating Diseases

Background and ObjectiveTo elucidate the relationship between melanoma cell adhesion molecule (MCAM)-expressing lymphocytes and pathogenesis of CNS inflammatory demyelinating diseases (IDDs).MethodsPatients with multiple sclerosis (MS) (n = 72) and neuromyelitis optica spectrum disorder (NMOSD, n = 29) were included. We analyzed the frequency and absolute numbers of MCAM+ lymphocytes (memory helper T [mTh] cells, naive helper T cells, CD8+ T cells, and B cells) in the peripheral blood (PB) and the CSF of patients with MS and NMOSD, treated with/without disease-modifying drugs (DMDs) or steroids, using flow cytometry.ResultsThe frequency of MCAM+ cells was higher in the mTh cell subset than that in other lymphocyte subsets. A significant increase in the frequency and the absolute number of MCAM+ mTh cells was observed in the PB of patients with NMOSD, whereas no increase was observed in the PB of patients with MS. The frequency of CSF MCAM+ mTh cells was higher in relapsing patients with MS and NMOSD than that in the control group. Although there was no difference in the frequencies of MCAM+ lymphocytes among the DMD-treated groups, fingolimod decreased the absolute number of MCAM+ lymphocytes.DiscussionMCAM+ mTh cells were elevated in the CSF of relapsing patients with MS and in both the PB and CSF of patients with NMOSD. These results indicate that MCAM contributes to the pathogenesis of MS and NMOSD through different mechanisms. MCAM could be a therapeutic target of CNS IDDs, and further study is needed to elucidate the underlying mechanism of MCAM in CNS IDD pathogenesis.

Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer

Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.

Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

In this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plasmid DNA in the cytosol-activating DNA sensors. The effects and underlying mechanisms of therapy were evaluated in more immunogenic B16F10 melanoma and less immunogenic TS/A carcinoma. The silencing of MCAM potentiated the effect of irradiation (IR) in both tumor models. Combined therapy resulted in 81% complete responses (CR) in melanoma and 27% CR in carcinoma. Moreover, after the secondary challenge of cured mice, 59% of mice were resistant to challenge with melanoma cells, and none were resistant to carcinoma. Combined therapy reduced the number of blood vessels; induced hypoxia, apoptosis, and necrosis; and reduced cell proliferation in both tumor models. In addition, the significant increase of infiltrating immune cells was observed in both tumor models but more so in melanoma, where the expression of IL-12 and TNF-α was determined as well. Our results indicate that the combined therapy exerts both antiangiogenic and immune responses that contribute to the antitumor effect. However, tumor immunological status is crucial for a sufficient immune system contribution to the overall antitumor effect.