RESUMO
Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-κB-dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8(+) T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-κB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-κB-mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/biossíntese , NF-kappa B/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Linhagem Celular Tumoral , Docetaxel , Feminino , Humanos , Camundongos , NF-kappa B/imunologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Taxoides/administração & dosagem , Taxoides/farmacologia , Transcriptoma/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As nanomaterials are developed and applied, their potential for health hazards needs to be determined. In the present study, we used commercial nude multi-walled carbon nanotubes (MWCNTs) trimmed to a short length (50-200 nm; s-MWCNTs) and synthesized functionalized MWCNTs with polyethylene glycol (PEG) (s-MWCNTs-PEG). We then studied the toxic effects of s-MWCNTs and s-MWCNTs-PEG on cultured cells and in a mouse model. Peripheral haemograms and various biochemical markers of the heart, liver and kidney were measured. We found no toxicity of either type of nanotube on the viability of human SKBR-3 breast carcinoma cells or control cells. There were no differences in vivo on inflammatory responses, the coagulation system, haemograms or vital organ functions between the test and control groups. Additionally, we found no toxicity of these nanotubes on male mouse sperm production or mutagenesis in the long term. In conclusion, both s-MWCNTs and s-MWCNTs-PEG displayed good in vitro and in vivo biocompatibility, making future applications in biology and clinical therapy as a carrier for drug delivery feasible.
