Suppression of 4.1R enhances the potency of NKG2D-CAR T cells against pancreatic carcinoma via activating ERK signaling pathway

Abstract

Pancreatic carcinoma (PC) is one of the most common malignancies. Chimeric antigen receptor (CAR)-modified T cells has achieved remarkable efficacy in the treatment of hematological malignancies. However, lack of tumor-specific targets and the existence of inhibitory factors limit the function of CAR T cells when treating solid tumors. 4.1R has been reported to suppress the anti-tumor activity of T cell responses. In this study, we investigated the anti-tumor activity of 4.1R deletion in natural killer group 2D (NKG2D)-CAR T cells against PC. The CAR T cells were obtained by transfecting T cells with lentiviral vector carrying NKG2D-CAR, NC-NKG2D-CAR, or KD2-NKG2D-CAR. In vitro, NKG2D-CAR T cells showed higher cytotoxicity than Mock T cells. However, compared to NKG2D-CAR T cells, furtherly higher cytotoxicity against PC cells in a dose-dependent manner was found in KD2-NKG2D-CAR T cells. In addition, the proliferation rate and cytotoxic activity of KD2-NKG2D-CAR T cells were significantly higher than those of NKG2D-CAR T cells. Besides, the inhibitory receptors PD-1 and TIM-3 were expressed in lower level on KD2-NKG2D-CAR T cells. In vivo, KD2-NKG2D-CAR T cells suppressed tumor growth more effectively in a xenograft model compared to NKG2D-CAR T cells. Mechanistically, 4.1R regulated CAR T cell function via activating ERK signaling pathway. Therefore, the study provides a new idea to enhance the anti-tumor efficiency of CAR T therapy.

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

“…Microbial molecules can regulate immune cell motility, and valeric acid and butyric acid can increase the antitumor activity of CD8+ CAR T cells ( 60 ). Second-generation KD2-natural killer group 2D (NKG2D)-CAR T cells exhibited a stronger antitumor activity compared with first-generation NKG2D-CAR T cells in a pancreatic cancer xenograft model ( 20 ). Thus, CAR T-cell therapy can inhibit cancer progression in pancreatic cancer, circumvent drug resistance arising from conventional treatments, and has great potential in clinical applications in the future.…”

“…Animal models with xenotransplantation, in situ transplantation animal models, and gene editing animal models are the more commonly used models to study CAR T-cell therapy. In bile duct cancer, pancreatic cancer, and gastric cancer, xenograft animal models are commonly used to show the therapeutic efficacy of CAR T-cell therapy ( 20 , 53 , 60 , 63 , 72 , 73 ).…”

“…As these cancers are largely refractory to conventional treatment, bile duct, pancreatic, and gastric cancers have been treated with CAR T-cell therapy ( 19 ). In most preclinical studies, researchers have used xenograft models to test CAR T-cell therapy in treating bile duct, pancreatic, and gastric cancers ( 20 ).…”

Modulating Cholesterol Metabolism via ACAT1 Knockdown Enhances Anti-B-Cell Lymphoma Activities of CD19-Specific Chimeric Antigen Receptor T Cells by Improving the Cell Activation and Proliferation

“…Although both shRNA technology and CRISPR-Cas9 are powerful tools used for gene manipulation, we have utilized shRNA since some studies have mentioned that shRNAs are coupled with fewer off-target effects compared with CRISPR-Cas9. Additionally, we have applied shRNA technology previously against solid tumors and have obtained promising results [ 40 ]. Interestingly, CD19-CAR T cells with silencing of ACAT1 had a stronger killing ability.…”

Induced pluripotent stem cells as natural biofactories for exosomes carrying miR-199b-5p in the treatment of spinal cord injury

“…Hgf, a hepatotropic factor, is a tumor-related gene and participated in many diseases, such as tumors and the cardiovascular system ( Nakamura and Mizuno, 2010 ; Qu et al, 2020 ; Xu et al, 2021 ). For example, Hgf/MET pathway has become an effective target and biomarker in many cancers ( Moosavi et al, 2019 ; Tao et al, 2020 ; Gao et al, 2021 ). In ischemic injury, Hgf and MET protect the heart by activating PI3K/Akt and MAPK signaling pathways ( Gallo et al, 2015 ; Cai et al, 2022 ).…”