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Published on: January 7, 2019
Treatment of Conjunctival Melanoma Cell Lines With a Light-Activated Virus-Like Drug Conjugate Induces Immunogenic
Sen Ma1, Ruben V Huis In't Veld2,3, Elisabet de Los Pinos4
1Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Purpose:
Conjunctival melanoma (CJM) is a rare malignant ocular surface tumor, which often leads to local recurrences and metastases. In murine models of subcutaneous tumors, treatment with a novel virus-like drug conjugate (VDC; Bel-sar) showed a dual mechanism of action with direct tumor cell killing as well as stimulation of an antitumoral immune response. Bel-sar is currently being evaluated for the treatment of primary uveal melanoma and indeterminate nevi in a phase III clinical trial. We determined whether Bel-sar also has direct antitumor efficiency and a potential immunostimulatory capacity in CJM cells.
Methods:
Three human tumor-derived CJM lines were used. Bel-sar's subcellular and intracellular locations were determined with tracers. Following light activation of Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were assessed. Treated tumor cells were co-cultured with THP-1 derived macrophages to assess tumor-cell phagocytosis.
Results:
Bel-sar was bound and internalized by CJM cells and subsequently found in the cell membrane, lysosome, Golgi apparatus, and mitochondria. Bel-sar activation induced near complete cell death with half-maximal inhibitory concentration (IC50) values between 30 pM and 60 pM. Finally, light-activated Bel-sar enhanced exposure of DAMPs, including calreticulin, heat shock protein 90, and stimulated phagocytosis by macrophages.
Conclusions:
Treatment with a novel VDC (Bel-sar) induced pro-immunogenic cell death in all three CJM cell lines. The in vitro cytotoxicity was accompanied by exposure of DAMPs, suggesting Bel-sar is a potential treatment for CJM by a dual mechanism of action. This dual mechanism may provide a targeted and direct killing of tumor cells and induce an immune response which might decrease local recurrences and metastasis.
Insights
A novel virus-like drug conjugate (Bel-sar) effectively kills conjunctival melanoma cells and stimulates an immune response. This dual action offers a promising new treatment strategy for this rare ocular cancer, potentially reducing recurrence and metastasis.
Area of Science:
- Ophthalmology
- Oncology
- Immunology
Background:
- Conjunctival melanoma (CJM) is a rare ocular surface malignancy associated with high rates of local recurrence and metastasis.
- Virus-like drug conjugates (VDCs) like Bel-sar have shown promise in preclinical models, exhibiting direct tumor cell killing and immune stimulation.
- Bel-sar is currently under investigation for uveal melanoma, but its efficacy in CJM requires specific evaluation.
Purpose of the Study:
- To investigate the direct antitumor efficiency of Bel-sar in conjunctival melanoma (CJM) cells.
- To assess the potential immunostimulatory capacity of Bel-sar in CJM.
- To determine if Bel-sar induces pro-immunogenic cell death in CJM.
Main Methods:
- Utilized three human tumor-derived CJM cell lines for in vitro studies.
- Determined Bel-sar's subcellular localization using fluorescent tracers.
- Assessed Bel-sar-induced cytotoxicity and damage-associated molecular pattern (DAMP) exposure upon light activation.
- Evaluated macrophage phagocytosis of Bel-sar-treated CJM cells.
Main Results:
- Bel-sar was internalized by CJM cells and localized to various organelles, including lysosomes and mitochondria.
- Light-activated Bel-sar demonstrated potent cytotoxicity, with IC50 values in the picomolar range.
- Bel-sar treatment significantly enhanced the exposure of DAMPs (e.g., calreticulin, HSP90) and promoted macrophage phagocytosis.
Conclusions:
- Bel-sar induces pro-immunogenic cell death in CJM cell lines, indicating direct antitumor activity.
- The observed DAMPs exposure suggests Bel-sar can stimulate an antitumoral immune response.
- Bel-sar presents a potential dual-action therapeutic strategy for CJM, targeting tumor cells directly while also harnessing the immune system to combat recurrence and metastasis.
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