ORIGINAL RESEARCH article

Front. Immunol.

Sec. T Cell Biology

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1498706

This article is part of the Research TopicDrug Development for Pancreatic Cancer: Novel Targets, Drug Candidates and MechanismsView all 4 articles

Co-expression of IL-15/IL-15Ra complex enhances NKG2D-CAR T cell-mediated anti-pancreatic cancer immunity by activating the JAK/STAT5 signaling pathway

Provisionally accepted
Wenzheng  JiangWenzheng Jiang*Yiran  ChenYiran ChenChenxu  JinChenxu JinDandan  GuoDandan GuoXinhui  HuiXinhui HuiYuzhou  JiYuzhou JiYunhe  HuangYunhe HuangMin  XueMin XueYaoxin  GaoYaoxin GaoYaojun  RenYaojun RenHaizhen  LinHaizhen LinYing  ZhouYing Zhou
  • East China Normal University, Shanghai, China

The final, formatted version of the article will be published soon.

The application of CAR T therapy has significantly improved the efficacy of hematological tumors. However, there are still some challenges in the treatment of solid tumors, mainly because the complex immune microenvironment affects the proliferation of T cells, making T cells unable to function well. IL-15 has been reported to be a cytokine that can activate T cells and promote the proliferation and survival of T cells, especially CD8 + T cells. The complex formed by the high-affinity binding of IL-15 and IL-15Rα can bind to IL-2/IL-15Rb/g heterodimer on the surface of T cells, thereby activating downstream signaling pathways in T cells. In this study, we explored the activity of NKG2D-CAR T expressing IL-15/IL-15Rα complex (IL15C) on pancreatic cancer. The results of in vitro experiments showed that CAR T cells expressing IL15C had a stronger killing effect on tumor cells and showed a dose-dependent effect. In addition, the proliferation and anti-apoptosis levels of CAR T cells were enhanced after the co-expression of IL15C. IL15C regulates the function of T cells by activating the JAK/STAT5 signaling pathway of T cells. In vivo experiments showed that IL15C-NKG2D-CAR T cells could better inhibit tumor growth than the control group. This study provides a new idea for improving the efficacy of CAR T cells in the treatment of pancreatic cancer.

Keywords: NKG2D, CAR T, IL-15, Pancreatic carcinoma, JAK/STAT5

Received: 19 Sep 2024; Accepted: 04 Jun 2025.

Copyright: © 2025 Jiang, Chen, Jin, Guo, Hui, Ji, Huang, Xue, Gao, Ren, Lin and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Wenzheng Jiang, East China Normal University, Shanghai, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.