Case of metastatic uveal melanoma in which an antitumor effect appeared after ipilimumab discontinuation due to autoimmune hypophysitis

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with high metastasis rates. The O6-methylguanine DNA methyl transferase (MGMT) is involved in chemoresistance of Dacarbazine (DTIC) treatment. Our previous study found that the combination of oncolytic adenovirus H101 and DTIC in the treatment of UM cells shows a synergistic antitumor effect mainly though down-regulation of MGMT. MGMT knockdown by shRNAs increases the sensitivity of uveal melanoma cells to DTIC treatment. The protein hemostasis of MGMT is important for the antitumor effect of DTIC. Tripartite motif-containing protein 72 (TRIM72) belongs to the tripartite motif (TRIM) proteins family and was identified as a novel E3 ligase for MGMT, which interacts with and mediates the ubiquitination of MGMT. TRIM72 knockdown increases the protein levels of MGMT, while reduces the ubiquitination of MGMT. Further study indicated that MGMT is highly expressed in UM cells, and the protein levels of MGMT and TRIM72 shows a negative correlation. UM cells that ectopically expressing TRIM72 shows increased sensitivity to DTIC treatment, which is consistent with the antitumor affect exhibited by H101. These results suggest that TRIM72 is a promising therapeutic target for UM treatment.

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Features of the lymphocytic microenvironment in metastatic uveal melanoma

Уральский медицинский журнал ◽

10.52420/2071-5943-2021-20-2-36-42 ◽

2021 ◽

Vol 20 (2) ◽

pp. 36-42

Author(s):

A. Y. Shamanova ◽

E. L. Kazachkov ◽

I. Е. Panova ◽

A. V. Vazhenin ◽

Т. N. Shamaeva ◽

...

Keyword(s):

Immune Response ◽

Uveal Melanoma ◽

Antitumor Effect ◽

Primary Melanoma ◽

Distant Metastases ◽

Melanoma Cells ◽

The Body ◽

Immune Reactivity ◽

Tumor Metastases ◽

Cd4 Lymphocytes

Introduction. Uveal melanoma is a malignant neoplasm of the vascular tract of the eye. Prevention of metastasis of this tumor is one of the main tasks in order to increase the rates of relapse-free survival of patients. Despite the pronounced immunosuppressive activity of uveal melanoma cells, its lymphocytic microenvironment exerts its antitumor effect.Aim of the study. Compare the lymphocytic microenvironment of primary uveal melanomas and distant metastases (to the liver).Мaterials and methods. The tissue material of choroid melanoma after enucleation and the material of tumor metastases for the period 2013-2018 were studied. An immunohistochemical study was performed using CD8, CD4, and CD56 markers for the qualitative and quantitative assessment of lymphocytes in the tumor stroma.Results. Differences were found in the lymphocytic infiltration of the uveal melanoma stroma and its distant metastases. A statistically significantly greater representation of CD4, CD8-lymphocytes and CD56 cells in tumor metastases than in primary melanoma tissue samples, with CD4-lymphocytes predominant. A direct high-strength correlation was registered between the number of CD4-lymphocytes and CD8-lymphocytes.Discussion. Malignant cells actively modify their cellular and stromal-vascular environment, ensuring their active growth and reproduction. The question of the immune reactivity of the surrounding cells in relation to uveal melanoma remains debatable. According to our data, which is consistent with a number of other studies, uveal melanoma cells do not completely evade the body's immune response. Thus, the determination of possible points of antitumor exposure can be based on a detailed study of the microenvironment of uveal melanoma. Conclusions. The pronounced lymphocytic infiltrate found in uveal melanoma metastases in comparison with the primary tumor indicates an active immune response of the body to the tumor. These results of our study confirm the importance of further studying the immune-mediated antitumor effect on uveal melanoma and the need to investigate possible approaches to immunotherapy.

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