Local radiotherapy polarized tumor-associated macrophages enhance the efficacy of Claudin18.2-targeted CAR-T therapy in pancreatic cancer.

IF 2 4区 医学 Q3 GASTROENTEROLOGY & HEPATOLOGY
Journal of gastrointestinal oncology Pub Date : 2025-08-30 Epub Date: 2025-08-27 DOI:10.21037/jgo-2025-564
Xiaokang Zhang, Hongtai Shi, Leran Qiu, Zhunyi Gao, Jiahe Xu, Xingyu Zhou, Zeya Xia, Ganesh Radhakrishna, Jiao Xue, Songbing Qin
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引用次数: 0

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and a 5-year survival rate of less than 10%. Its dense, immunosuppressive tumor microenvironment (TME) limits the effectiveness of conventional therapies, including immunotherapy. Chimeric antigen receptor T-cell (CAR-T) therapy targeting the tight junction protein claudin18.2 (CLDN18.2) has shown promise in preclinical PDAC studies, but its efficacy is severely constrained by immunosuppressive components in the TME, such as tumor-associated macrophages (TAMs). In addition to directly killing tumor cells, radiotherapy (RT) can modulate the TME, promote immune cell infiltration, and potentially enhance the efficacy of CAR-T in solid tumors. This study aimed to investigate the effects of combining RT with CLDN18.2-targeted CAR-T therapy for PDAC, focusing on elucidating whether RT can overcome the major barriers to immunotherapy in PDAC by reshaping the immunosuppressive TME and enhancing CAR-T infiltration and function.

Methods: Second-generation anti-CLDN18.2 CAR-Ts with high transduction efficiency were generated. In vitro, we assessed the cytotoxicity of CAR-Ts against PDAC cells expressing CLDN18.2 both with and without prior irradiation. In vivo, the combination of RT and CAR-T therapy was tested in PDAC-bearing mice, and survival and tumor growth were monitored. The immune response and TME were analyzed for CAR-T infiltration, effector function production [tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and granzyme B], and immune cell composition (Tregs, MDSCs, and M1 macrophages).

Results: In vitro, the CAR-Ts exhibited potent cytotoxicity against the CLDN18.2-positive PDAC cells, and the efficacy was enhanced in the irradiated PDAC cells compared to the non-irradiated control PDAC cells. In vivo, local RT combined with CAR-T therapy significantly prolonged survival and delayed tumor growth in the PDAC-bearing mice. Additionally, the combination therapy increased the CAR-T infiltration and effector functions. Local RT also reshaped the TME by increasing M1 macrophages and reducing M2 macrophages.

Conclusions: Local RT significantly enhanced the anti-tumor efficacy of CLDN18.2-targeted CAR-T therapy against PDAC. In vitro, RT increased CAR-T cytotoxicity against CLDN18.2-positive PDAC cells. In vivo, combining RT with CAR-T therapy prolonged survival and delayed tumor growth in tumor-bearing mice. This synergy resulted from RT promoting CAR-T infiltration and effector function, while reshaping the tumor microenvironment (TME) by increasing pro-inflammatory M1 macrophages and reducing immunosuppressive M2 macrophages. These findings show the potential of this combination approach as a promising therapeutic strategy for improving outcomes in PDAC patients.

局部放疗极化肿瘤相关巨噬细胞可增强claudin18.2靶向CAR-T治疗胰腺癌的疗效。
背景:胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)预后较差,5年生存率不足10%。其致密的免疫抑制肿瘤微环境(TME)限制了包括免疫治疗在内的常规治疗的有效性。靶向紧密连接蛋白CLDN18.2 (CLDN18.2)的嵌合抗原受体t细胞(CAR-T)疗法在临床前PDAC研究中显示出前景,但其疗效受到TME中免疫抑制成分(如肿瘤相关巨噬细胞(tam))的严重限制。放疗(RT)除了直接杀伤肿瘤细胞外,还可以调节TME,促进免疫细胞浸润,潜在地增强CAR-T治疗实体瘤的疗效。本研究旨在探讨RT联合cldn18.2靶向CAR-T治疗PDAC的效果,重点阐明RT能否通过重塑免疫抑制性TME,增强CAR-T浸润和功能,克服PDAC中免疫治疗的主要障碍。方法:制备高转导效率的第二代抗cldn18.2 car - t。在体外,我们评估了car - t对表达CLDN18.2的PDAC细胞的细胞毒性,无论是否事先照射。在体内,在携带pdac的小鼠中测试RT和CAR-T联合治疗,并监测生存和肿瘤生长。分析CAR-T浸润、效应功能产生[肿瘤坏死因子α (TNF-α)、干扰素γ (IFN-γ)和颗粒酶B]和免疫细胞组成(Tregs、MDSCs和M1巨噬细胞)的免疫应答和TME。结果:在体外,CAR-Ts对cldn18.2阳性的PDAC细胞表现出强大的细胞毒性,并且与未照射的对照PDAC细胞相比,照射后的PDAC细胞的效果增强。在体内,局部RT联合CAR-T治疗显著延长了pdac小鼠的生存期,延缓了肿瘤生长。此外,联合治疗增加了CAR-T浸润和效应物功能。局部RT还通过增加M1巨噬细胞和减少M2巨噬细胞重塑TME。结论:局部RT可显著增强cldn18.2靶向CAR-T治疗PDAC的抗肿瘤效果。在体外,RT增加了CAR-T细胞对cldn18.2阳性PDAC细胞的毒性。在体内,RT联合CAR-T治疗延长了荷瘤小鼠的生存期,延缓了肿瘤的生长。这种协同作用是由于RT促进CAR-T浸润和效应功能,同时通过增加促炎M1巨噬细胞和减少免疫抑制性M2巨噬细胞重塑肿瘤微环境(TME)。这些发现表明,这种联合治疗方法作为改善PDAC患者预后的有希望的治疗策略具有潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.20
自引率
0.00%
发文量
171
期刊介绍: ournal of Gastrointestinal Oncology (Print ISSN 2078-6891; Online ISSN 2219-679X; J Gastrointest Oncol; JGO), the official journal of Society for Gastrointestinal Oncology (SGO), is an open-access, international peer-reviewed journal. It is published quarterly (Sep. 2010- Dec. 2013), bimonthly (Feb. 2014 -) and openly distributed worldwide. JGO publishes manuscripts that focus on updated and practical information about diagnosis, prevention and clinical investigations of gastrointestinal cancer treatment. Specific areas of interest include, but not limited to, multimodality therapy, markers, imaging and tumor biology.
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