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

Sep 24, 2026

Uploaded by Connor

Despite the successful application of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, therapeutic efficacy in solid tumors remains limited due to an immunosuppressive tumor microenvironment and low density of specific tumor antigens. NKG2D CAR-T cells have shown promise in multiple cancers, but their application in gastric cancer requires further study. This work demonstrates that combining Dickkopf-1 (DKK1) inhibition with NKG2D-CAR-T produces synergistic, superior antitumor effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Background

CAR-T and NKG2D Rationale

Study Objective

Methods and Key Findings

Significance

Received: 12 December 2022 Revised: 13 March 2023 Accepted: 5 April 2023 DOI: 10. 1111/cas.15828 OR I G I NAL ART I C L E Combination therapy of DKK1 inhibition and NKG2D chimeric antigen receptor T cells for the treatment of gastric cancer Yipeng Zhang1 | Kaijie Liang1 | Xiaoyu Zhou2 | Xin Zhang1 | Hui Xu3 | Hongjiu Dai3 | Xueru Song1 | Xueyi Yang1 | Baorui Liu1 | Tao Shi1 | Jia Wei1,4 1Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China 2Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China 3 Nanjing Kaedi Biotherapeutics Co. Ltd. , Nanjing, China 4Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China Correspondence Jia Wei and Tao Shi, Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China. [Email:](Email: jiawei99@nju.edu.cn)[ jiawei99@nju.edu.cn](Email: jiawei99@nju.edu.cn) (JW); [151230030@smail. nju.edu.cn](151230030@smail. nju.edu.cn) (TS) Funding information National Natural Science Foundation of China, Grant/Award Number: 82073382; the Fundamental Research Funds for the Central Universities, Grant/Award Number: 0214-14380506 Abstract 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 NKG2DCAR-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. K E Y WO R D S combination immunotherapy, DKK1, gastric cancer, NKG2D-CAR-T, tumor microenvironment Abbreviations: AML, acute myeloid leukemia; CAR, chimeric antigen receptor; DKK1, Dickkopf-1; E:T, effector : target; FCM, flow cytometry; GC, gastric cancer; HNSC, head and necksquamous cell carcinoma; IFN-γ, γ-interferon; IHC, immunohistochemistry; MDSC, myeloid-derived suppressor cell; MFC, mouse forestomach carcinoma; MICA/B, MHC class I related chain A/B; NCG, NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt; NK, natural killer; NKG2D, natural killer group 2 member D; NKG2DL, natural killer group 2 member D ligand; NS, normal saline; NTD, nontransduced T cell; ORR, objective response rate; PD-1, programmed cell death protein; TIME, tumor immune microenvironment; TNF-α , tumor necrosis factor-α; ULBP1-6, UL16-binding protein 1–6. This

FAQs

Why is CAR-T therapy less effective for gastric cancer than for blood cancers?

Solid tumors, including gastric cancer, have a highly immunosuppressive tumor microenvironment and low density of specific tumor antigens, which limits efficacy.

What is the proposed combination strategy in this study?

The study combines DKK1 inhibition with NKG2D chimeric antigen receptor T cells to enhance antitumor activity in gastric cancer.

What effects does DKK1 inhibition have on gastric cancer immunity and NKG2D ligands?

DKK1 inhibition reverses the suppressive tumor immune microenvironment and upregulates NKG2D ligand expression in gastric cancer cell lines and tumor tissue in a xenograft mouse model.

Sep 24, 2026

Uploaded by Connor