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异位 CXCR2 表达细胞可提高 CAR-T 细胞的抗肿瘤效率并重塑胰腺导管腺癌的免疫微环境。

Ectopic CXCR2 expression cells improve the anti-tumor efficiency of CAR-T cells and remodel the immune microenvironment of pancreatic ductal adenocarcinoma.

机构信息

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Xu-Hui District, Shanghai, 200032, China.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.

出版信息

Cancer Immunol Immunother. 2024 Mar 2;73(4):61. doi: 10.1007/s00262-024-03648-y.

DOI:10.1007/s00262-024-03648-y
PMID:38430267
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10908625/
Abstract

BACKGROUND

Recent progressions in CAR-T cell therapy against pancreatic ductal adenocarcinoma (PDAC) remain disappointing, which are partially attributed to the immunosuppressive microenvironment including macrophage-mediated T cell repletion.

METHODS

We first characterized the expression patterns of macrophage-relevant chemokines and identified CXCR2 as the key factor regulating T cell trafficking and tumor-specific accumulation in PDAC microenvironment. After that, we synthesized and introduced a CXCR2 expression cascade into Claudin18.2 CAR-T cells and compared the behaviors of CAR-T cells in vitro and in vivo. The therapeutic potential of CXCR2 CAR-T was evaluated in two different allogeneic models: subcutaneous allografts and metastatic PDAC models.

RESULTS

The results showed that CXCR2 CAR-T not only reduced the size of allografted PDAC tumors, but also completely eliminated the formation of metastases. Lastly, we investigated the tumor tissues and found that expression of ectopic CXCR2 significantly improved tumor-targeted infiltration and residence of T cells and reduced the presence of MDSCs and CXCR2 + macrophages in PDAC microenvironment.

CONCLUSION

Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.

摘要

背景

嵌合抗原受体 T 细胞（CAR-T）疗法在治疗胰腺导管腺癌（PDAC）方面的最新进展仍然令人失望，部分原因是免疫抑制微环境，包括巨噬细胞介导的 T 细胞补充。

方法

我们首先对巨噬细胞相关趋化因子的表达模式进行了表征，并确定 CXCR2 是调节 PDAC 微环境中 T 细胞迁移和肿瘤特异性积累的关键因素。之后，我们合成并引入了 CXCR2 表达级联到 Claudin18.2 CAR-T 细胞中，并比较了 CAR-T 细胞在体外和体内的行为。在两种不同的同种异体模型中评估了 CXCR2 CAR-T 的治疗潜力：皮下同种异体移植和转移性 PDAC 模型。

结果

结果表明，CXCR2 CAR-T 不仅缩小了同种异体移植的 PDAC 肿瘤的大小，而且完全消除了转移的形成。最后，我们研究了肿瘤组织，发现异位 CXCR2 的表达显著改善了 T 细胞的肿瘤靶向浸润和驻留，并减少了 PDAC 微环境中 MDSCs 和 CXCR2+巨噬细胞的存在。

结论

我们的研究表明，异位 CXCR2 在提高 CAR-T 治疗原发性和转移性 PDAC 的效率方面发挥了重要作用，并部分逆转了免疫抑制微环境。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/eac10936d9e6/262_2024_3648_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/1e57ed6546f1/262_2024_3648_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/beb82956a271/262_2024_3648_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/0e40032f93c8/262_2024_3648_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/6d2c76d8d645/262_2024_3648_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/a3ec27feee7a/262_2024_3648_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/d1026a2edf6d/262_2024_3648_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/eac10936d9e6/262_2024_3648_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/1e57ed6546f1/262_2024_3648_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/beb82956a271/262_2024_3648_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/0e40032f93c8/262_2024_3648_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/6d2c76d8d645/262_2024_3648_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/a3ec27feee7a/262_2024_3648_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/d1026a2edf6d/262_2024_3648_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b77/10991877/eac10936d9e6/262_2024_3648_Fig7_HTML.jpg

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