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Published on: February 24, 2023
Mesenchymal stromal cells producing TNFα lack inhibitory effect against A375 experimental lung metastases
Abstract:
Cell-based anticancer therapy using mesenchymal stromal cells (MSCs) engineered to express therapeutic genes has a potential to target the cancer cells in vivo. Metastatic dissemination of melanoma remains a serious problem in the treatment. In our previous work we used MSCs overexpressing gene for tumor necrosis factor α (TNFα; MSCs/TNFα), and we achieved inhibition of melanoma xenograft growth when engineered MCSs/TNFα were coinjected with tumor cells subcutaneously. The TNFα as a pleiotropic cytokine induces apoptosis of tumor cells, creates "tumor resistant" microenvironment, enhances immune response and can have tumor destructive capacity in selected tumor types, especially in tumors of mesodermal origin.In this study we investigated the possibility of intravenously administered MCSs/TNFα to inhibit metastatic spread of A375 melanoma cells in the lungs. We confirmed elevated expression of TNFα transgene in the lung tissue 20 days after MCSs/TNFα intravenous infusion. We also documented that constitutive expression of TNFα transgene is able to neutralize the supportive effect of MSCs on melanoma cells growth. Metastatic spread of A375 melanoma cells in the lung was inhibited approximately to 50% after MCSs/TNFα i.v. administration in comparison to control group with parental MSCs supporting tumor growth. In conclusion, engineered MCSs/TNFα administered intravenously did not demonstrate significant antitumor effect against experimental melanoma lung metastases in this model settings.
Insights
Engineered mesenchymal stromal cells (MSCs) expressing tumor necrosis factor alpha (TNFα) showed potential in targeting melanoma. Intravenous administration of MSCs/TNFα partially inhibited melanoma lung metastases, but did not demonstrate a significant overall antitumor effect in this model.
Area of Science:
- Oncology
- Cell Therapy
- Immunotherapy
Background:
- Mesenchymal stromal cells (MSCs) engineered with therapeutic genes offer potential for in vivo cancer treatment.
- Metastatic melanoma remains a significant clinical challenge.
- Previous studies showed MSCs overexpressing tumor necrosis factor alpha (TNFα) inhibited melanoma xenografts when co-injected subcutaneously.
Purpose of the Study:
- To investigate the efficacy of intravenously administered MSCs engineered to express TNFα (MSCs/TNFα) in inhibiting the metastatic spread of A375 melanoma cells to the lungs.
- To evaluate the in vivo expression of the TNFα transgene in lung tissue following intravenous infusion of MSCs/TNFα.
Main Methods:
- A375 melanoma cells were used to establish lung metastases in a preclinical model.
- Engineered MSCs/TNFα or control MSCs were administered intravenously.
- TNFα transgene expression in lung tissue was confirmed.
- Melanoma lung metastasis burden was quantified and compared between groups.
Main Results:
- Elevated TNFα transgene expression was confirmed in lung tissue 20 days after MSCs/TNFα intravenous infusion.
- Constitutive TNFα expression neutralized the supportive effect of MSCs on melanoma cell growth.
- Intravenous administration of MSCs/TNFα resulted in approximately 50% inhibition of A375 melanoma lung metastases compared to the control group.
Conclusions:
- Engineered MSCs/TNFα administered intravenously did not demonstrate a significant overall antitumor effect against experimental melanoma lung metastases in this model.
- While partial inhibition of lung metastases was observed, further optimization is needed for effective clinical translation of this cell-based therapy.
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