Cargando…
Inhibition of Cholesterol Esterification Enzyme Enhances the Potency of Human Chimeric Antigen Receptor T Cells against Pancreatic Carcinoma
This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063140/ https://www.ncbi.nlm.nih.gov/pubmed/32181327 http://dx.doi.org/10.1016/j.omto.2020.01.008 |
Sumario: | This study aimed to assess the effectiveness of inhibiting cholesterol acyltransferase 1 (ACAT-1) in chimeric antigen receptor T (CAR-T) cells on potentiating the antitumor response against mesothelin (MSLN)-expressing pancreatic carcinoma (PC) cells. We engineered ACAT-1-inhibited CAR-T cells (CAR-T-1847 and CAR-T-1848) using the targeting MSLN CAR lentiviral vector and small interfering RNA (siRNA) targeting the conserved region of the ACAT-1 gene, and characterized the efficacy of these modified CAR-T cells in terms of the cytotoxicity and cytokine release of both MSLN-positive and MSLN-negative PC cells using in vitro methods and in vivo mouse xenografts. The ACAT-1-inhibited CAR-T-1847 and CAR-T-1848 cells showed a higher cytotoxicity at effector-to-target cell (E:T) ratios of 8:1 and 10:1, respectively, and induced a higher secretion of proinflammatory cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ) in vitro. In addition, bioluminescence imaging of tumor xenografts of ACAT-1-inhibited targeting MSLN CAR-T cells in MSLN-positive PC mice in vivo showed significant tumor regression, which is consistent with the in vitro observations. Our findings demonstrate a novel immunotherapeutic strategy involving the transplantation of ACAT-1-inhibited targeting MSLN CAR-T cells and the feasibility of enhancing the antitumor potency of CAR-T through the novel strategy. |
---|