Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy

被引：1

作者：

Dong, Lei ^{[1
,2
]}

Zhu, Yini ^{[3
]}

Zhang, Haoge ^{[4
]}

Gao, Lin ^{[4
]}

Zhang, Zhiqi ^{[4
]}

Xu, Xiaoxuan ^{[4
]}

Ying, Leqian ^{[1
,2
]}

Zhang, Lu ^{[1
,2
]}

Li, Yue ^{[5
]}

Yun, Zhengcheng ^{[1
,2
]}

Zhu, Danqi ^{[4
]}

Han, Chang ^{[4
]}

Xu, Tingting ^{[1
,2
]}

Yang, Hui ^{[6
]}

Ju, Shenghong ^{[4
]}

Chen, Xiaoyuan ^{[4
,7
,8
,9
,10
,11
,12
,13
,14
]}

Zhang, Haijun ^{[1
,2
]}

Xie, Jinbing ^{[4
]}

机构：

[1] Southeast Univ, Zhongda Hosp, Med Sch, Nurturing Ctr Jiangsu Prov,State Lab AI Imaging &, 87 Dingjiaqiao, Nanjing 210009, Peoples R China

[2] Southeast Univ, Zhongda Hosp, Med Sch, Dept Oncol, 87 Dingjiaqiao, Nanjing 210009, Peoples R China

[3] Southeast Univ, Med Sch, Dept Microbiol & Immunol, Nanjing 210009, Jiangsu, Peoples R China

[4] Southeast Univ, Zhongda Hosp, Basic Med Res & Innovat Ctr, Med Sch,Dept Radiol,Minist Educ,State Key Lab Digi, Nanjing, Peoples R China

[5] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China

[6] Southeast Univ, Med Sch, Dept Biochem & Mol Biol, Nanjing, Peoples R China

[7] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Diagnost Radiol, Singapore 119074, Singapore

[8] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119074, Singapore

[9] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Chem & Biomol Engn, Singapore 119074, Singapore

[10] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biomed Engn, Singapore 119074, Singapore

[11] Natl Univ Singapore, Coll Design & Engn, Singapore 119074, Singapore

[12] Natl Univ Singapore, NUS Ctr Nanomed, Yong Loo Lin Sch Med, Nanomed Translat Res Program, Singapore 117597, Singapore

[13] Natl Univ Singapore, Clin Imaging Res Ctr, Ctr Translat Med, Yong Loo Lin Sch Med, Singapore 117599, Singapore

[14] ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore

来源：

ADVANCED MATERIALS | 2024年 / 36卷 / 44期

基金：

中国国家自然科学基金;

关键词：

CXCL10; glioblastoma; IL-2; immune checkpoint inhibitors; immunosuppressive microenvironment; low-frequency focused ultrasound; T-cell exhaustion; THERAPY;

D O I：

10.1002/adma.202407235

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8(+) T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8(+) T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8(+) T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8(+) T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8(+) T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8(+) T cells, which may present a promising strategy for brain-tumor immunotherapy.

引用

页数：15