“…The death or necrosis of tumor cells is caused by these DNA adducts, which have an effect on several transduction pathways [ 22 ]. CBP has been used in combination with antibodies, natural compounds, and other chemotherapeutic agents in therapies against various cancers [ 23 , 24 , 25 , 26 ]. Nano systems such as gelatin nanoparticles, chitosan nanoparticles, and targeted liposomes have been used to deliver CBP for better targeting and decreased side effects [ 23 , 27 , 28 ].…”
In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, and atomic force microscopy imaging revealed vesicles with a spherical form and sizes meeting the criteria of exosomal EVs. Further, Western blot studies demonstrated the presence of regular EV markers along with specific NK markers (perforin and granzyme). EVs were also characterized by proteomic analysis, which demonstrated that EVs had proteins for natural killer cell-mediated cytotoxicity (Granzyme B) and T cell activation (perforin and plastin-2). Gene oncology analysis showed that these differentially expressed proteins are involved in programmed cell death and positive regulation of cell death. Further, isolated NK-EVs were cytotoxic to H1975R cells in vitro in 2D and 3D cell cultures. CBP’s IC50 was reduced by approximately in 2D and 3D cell cultures when combined with NK-EVs. The EVs were then combined with CBP and administered by i.p. route to H1975R tumor xenografts, and a significant reduction in tumor volume in vivo was observed. Our findings show for the first time that NK-EVs target the PD-L1/PD-1 immunological checkpoint to induce apoptosis and anti-inflammatory response by downregulation of SOD2, PARP, BCL2, SET, NF-κB, and TGF-ß. The ability to isolate functional NK-EVs on a large scale and use them with platinum-based drugs may lead to new clinical applications. The results of the present study suggest the possibility of the combination of NK-cell-derived EVs and CBP as a viable immunochemotherapeutic strategy for resistant cancers.
“…The death or necrosis of tumor cells is caused by these DNA adducts, which have an effect on several transduction pathways [ 22 ]. CBP has been used in combination with antibodies, natural compounds, and other chemotherapeutic agents in therapies against various cancers [ 23 , 24 , 25 , 26 ]. Nano systems such as gelatin nanoparticles, chitosan nanoparticles, and targeted liposomes have been used to deliver CBP for better targeting and decreased side effects [ 23 , 27 , 28 ].…”
In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, and atomic force microscopy imaging revealed vesicles with a spherical form and sizes meeting the criteria of exosomal EVs. Further, Western blot studies demonstrated the presence of regular EV markers along with specific NK markers (perforin and granzyme). EVs were also characterized by proteomic analysis, which demonstrated that EVs had proteins for natural killer cell-mediated cytotoxicity (Granzyme B) and T cell activation (perforin and plastin-2). Gene oncology analysis showed that these differentially expressed proteins are involved in programmed cell death and positive regulation of cell death. Further, isolated NK-EVs were cytotoxic to H1975R cells in vitro in 2D and 3D cell cultures. CBP’s IC50 was reduced by approximately in 2D and 3D cell cultures when combined with NK-EVs. The EVs were then combined with CBP and administered by i.p. route to H1975R tumor xenografts, and a significant reduction in tumor volume in vivo was observed. Our findings show for the first time that NK-EVs target the PD-L1/PD-1 immunological checkpoint to induce apoptosis and anti-inflammatory response by downregulation of SOD2, PARP, BCL2, SET, NF-κB, and TGF-ß. The ability to isolate functional NK-EVs on a large scale and use them with platinum-based drugs may lead to new clinical applications. The results of the present study suggest the possibility of the combination of NK-cell-derived EVs and CBP as a viable immunochemotherapeutic strategy for resistant cancers.
Background: As dendritic cells (DCs) are the major antigen-presenting cells of the immune system, understanding their role in esophageal cancer is essential for the development of preventative and treatment strategies. This study investigated the expression level and clinical value of tumor infiltrating dendritic cells (TIDCs) in tumor tissues of patients with esophageal cancer.Methods: From January 2019 to January 2021, 184 patients with esophageal cancer treated were prospectively enrolled as the observation group and 184 patients with benign esophageal tumors were selected as the control group. Tumor tissue samples were obtained and the expression level and phenotypes of the TIDCs were analyzed. The correlation between TIDC expression and clinical characteristics of patients with esophageal cancer was investigated.Results: The density of the TIDCs in the observation group was lower than that in the control group (8.76±2.25 vs. 9.97±2.19; P=0.000). Furthermore, the percentage of major histocompatibility complex-II (MHC-II) positive DCs and the percentage of CD54 positive DCs were relatively lower in the observation group compared to the control group (6.60%±2.12% vs. 9.34%±2.41%; P=0.000 and 7.41%±2.36% vs. 9.98%±2.47%; P=0.000, respectively). Esophageal cancer patients with lymph node metastasis had lower TIDC density, lower percentage of MHC-II positive DCs, and lower percentage of CD54 positive DCs compared to patients without node metastasis (P<0.05). Patients with stage III esophageal cancer also showed significantly lower TIDC density, lower percentage of MHC-II positive DCs, and lower percentage of CD54 positive DCs compared to patients with stage I/II esophageal cancer (P<0.05). Esophageal cancer patients with tumor diameter ≥4 cm presented with decreased TIDC density, decreased percentage of MHC-II positive DCs, and decreased percentage of CD54 positive DCs compared to patients with tumor diameter <4 cm (P<0.05). In addition, the density of TIDCs, the percentage of MHC-II positive DCs, and the percentage of CD54 positive DCs were significantly negatively correlated with the percentage of CD4+ T-lymphocytes and positively correlated with the percentage of CD8+ T-lymphocytes (P<0.05).Conclusions: Patients with esophageal cancer had low expression and function of TIDCs, and this was related to the imbalance of T-lymphocyte subsets, lymph node metastasis, TNM stage, and lesion size.
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