Cytochalasin B-Induced Membrane Vesicles from Human Mesenchymal Stem Cells Overexpressing IL2 Are Able to Stimulate CD8+ T-Killers to Kill Human Triple Negative Breast Cancer Cells

Abstract

Interleukin 2 (IL2) was one of the first cytokines used for cancer treatment due to its ability to stimulate anti-cancer immunity. However, recombinant IL2-based therapy is associated with high systemic toxicity and activation of regulatory T-cells, which are associated with the pro-tumor immune response. One of the current trends for the delivery of anticancer agents is the use of extracellular vesicles (EVs), which can carry and transfer biologically active cargos into cells. The use of EVs can increase the efficacy of IL2-based anti-tumor therapy whilst reducing systemic toxicity. In this study, human adipose tissue-derived mesenchymal stem cells (hADSCs) were transduced with lentivirus encoding IL2 (hADSCs-IL2). Membrane vesicles were isolated from hADSCs-IL2 using cytochalasin B (CIMVs-IL2). The effect of hADSCs-IL2 and CIMVs-IL2 on the activation and proliferation of human peripheral blood mononuclear cells (PBMCs) as well as the cytotoxicity of activated PBMCs against human triple negative cancer MDA-MB-231 and MDA-MB-436 cells were evaluated. The effect of CIMVs-IL2 on murine PBMCs was also evaluated in vivo. CIMVs-IL2 failed to suppress the proliferation of human PBMCs as opposed to hADSCs-IL2. However, CIMVs-IL2 were able to activate human CD8+ T-killers, which in turn, killed MDA-MB-231 cells more effectively than hADSCs-IL2-activated CD8+ T-killers. This immunomodulating effect of CIMVs-IL2 appears specific to human CD8+ T-killer cells, as the same effect was not observed on murine CD8+ T-cells. In conclusion, the use of CIMVs-IL2 has the potential to provide a more effective anti-cancer therapy. This compelling evidence supports further studies to evaluate CIMVs-IL2 effectiveness, using cancer mouse models with a reconstituted human immune system.

Tropism of Extracellular Vesicles and Cell-Derived Nanovesicles to Normal and Cancer Cells: New Perspectives in Tumor-Targeted Nucleic Acid Delivery

“…Indeed, the MSCderived CINVs retained their surface protein architecture well, which suggested their suitability for the creation of CINVs. These data are in good agreement with previous observations [36,46,76].…”

Analysis of the Interaction of Human Neuroblastoma Cell-Derived Cytochalasin B Induced Membrane Vesicles with Mesenchymal Stem Cells Using Imaging Flow Cytometry

“…On the one hand, the exchange of vesicles between stem and tumor cells leads to the development of drug resistance and enhances tumor aggression. On the other hand, these fundamental properties of cell communication can open up new therapeutic approaches to the delivery of drugs toward the tumor [1,14,40,41].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Pleiotropic Impacts on Breast Cancer Occurrence, Development, and Therapy

“…On the contrary, there is also evidence that MSC-EVs are involved in inducing immune responses. For instance, it was reported that AT-MSC-EVs with overexpressed human IL-2, a cytokine that regulates immune cells activation and proliferation, can stimulate the proliferation of CD8+ T-killer cells, thereby effectively killing TNBC cells [ 95 ]. In conclusion, MSC-EVs may act as both stimulatory and/or inhibitory mediators of immune cells in BC.…”

“…MSC-MVs can be packed into polycaprolactone (PCL) nanofibers and thus released for a long time, and this apoptotic effect is maintained in cancer cells cultured on PCL-MVs nanofibers, suggesting that AT-MSC-MVs can be used as an in situ inhibitor rather than as a chemo-drug [ 70 ]. Similarly, Chulpanova et al reported that cytochalasin B was also capable of inducing MSCs to release EVs for increasing the yield of EVs [ 95 ]. In addition, BC patients after lumpectomy may require augmentation or surgical cosmetic procedure with scaffolds containing MVs, which have two potential advantages: the ability to fill the cavity created by the removal of cancerous breast tissue as well as causing the death of probable BC cells [ 70 ].…”