Journal Article

Combination therapy of DKK1 inhibition and NKG2D chimeric antigen receptor T cells for the treatment of gastric cancer

Zhang, Xin, Yang, Xueyi, Liu, Baorui, Liang, Kaijie, Zhou, Xiaoyu, Wei, Jia, Song, Xueru, Shi, Tao, Xu, Hui, Zhang, Yipeng, Dai, Hongjiu

2023

Overview

Despite the successful application of chimeric antigen receptor (CAR)‐T cell therapy in hematological malignancies, the treatment efficacy in solid tumors remains unsatisfactory, largely due to the highly immunosuppressive tumor microenvironment and low density of specific tumor antigens. Natural killer group 2 member D (NKG2D) CAR‐T cells have shown promising treatment effects on several cancers such as lymphoma and multiple myeloma. However, the application and efficacy of NKG2D‐CAR‐T cells in gastric cancer (GC) still needs further exploration. This study identified a novel combination immunotherapy strategy with Dickkopf‐1 (DKK1) inhibition and NKG2D‐CAR‐T cells, exerting synergistic and superior antitumor effect in GC. We show that the baseline expression of NKG2D ligands (NKG2DLs) is at low levels in GC tissues from The Cancer Genome Atlas and multiple GC cell lines including NCI‐N87, MGC803, HGC27, MKN45, SGC7901, NUGC4, and AGS. In addition, DKK1 inhibition by WAY‐262611 reverses the suppressive tumor immune microenvironment (TIME) and upregulates NKG2DL expression levels in both GC cell lines and GC tissues from a xenograft NCG mouse model. DKK1 inhibition in GC cells markedly improves the immune‐activating and tumor‐killing ability of NKG2D‐CAR‐T cells as shown by cytotoxicity assays in vitro. Moreover, the combination therapy of NKG2D‐CAR‐T and WAY‐262611 triggers superior antitumor effects in vivo in a xenograft NCG mouse model. In sum, our study reveals the role of DKK1 in remodeling GC TIME and regulating the expression levels of NKG2DLs in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D‐CAR‐T cell therapy, which could bring new breakthroughs for GC immunotherapy. Our study reveals the role of Dickkopf‐1 (DKK1) in remodeling gastric cancer (GC) tumor immune microenvironment and regulating the expression levels of natural killer group 2 member D (NKG2D) ligands in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D‐ chimeric antigen receptor‐T cell therapy, which could bring new breakthroughs for GC immunotherapy.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Antigen (tumor-associated) / Antigens / Antitumor activity / Cancer therapies / Cell culture / Cell therapy / Chimeric antigen receptors / combination immunotherapy / Cytotoxicity / DKK1 / Dkk1 protein / Gastric cancer / Genomes / Hematology / Immunocompetence / Immunotherapy / Investigations / Ligands / Liver cancer / Lymphocytes / Lymphocytes T / Lymphoma / Malignancy / Medical prognosis / Multiple myeloma / Natural killer cells / NKG2D‐CAR‐T / Original / ORIGINAL ARTICLES / Solid tumors / Statistical analysis / Statistical significance / Tumor microenvironment / Tumor necrosis factor-TNF / Tumors / Xenografts