Low-intensity focused ultrasound targeted microbubble destruction reduces tumor blood supply and sensitizes anti-PD-L1 immunotherapy

作者全名："Wu, Nianhong; Cao, Yuting; Liu, Ying; Zhou, Ying; He, Hongye; Tang, Rui; Wan, Li; Wang, Can; Xiong, Xialin; Zhong, Linhong; Li, Pan"

作者地址："[Wu, Nianhong; Cao, Yuting; Liu, Ying; Zhou, Ying; He, Hongye; Tang, Rui; Wan, Li; Wang, Can; Xiong, Xialin; Zhong, Linhong; Li, Pan] Chongqing Med Univ, Inst Ultrasound Imaging, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing, Peoples R China; [Wu, Nianhong; Cao, Yuting; Liu, Ying; Zhou, Ying; He, Hongye; Tang, Rui; Wan, Li; Wang, Can; Xiong, Xialin; Zhong, Linhong; Li, Pan] Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing, Peoples R China; [Liu, Ying] Third Peoples Hosp Chengdu City, Dept Ultrasound, Chengdu, Peoples R China"

通信作者："Li, P (通讯作者)，Chongqing Med Univ, Inst Ultrasound Imaging, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing, Peoples R China.; Li, P (通讯作者)，Chongqing Med Univ, Dept Ultrasound, Affiliated Hosp 2, Chongqing, Peoples R China."

来源：FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY

ESI学科分类：Multidisciplinary

WOS号：WOS:000980611400001

JCR分区：Q1

影响因子：5.7

年份：2023

卷号：11

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：immune checkpoint blockade; immune infiltration; antivascular therapy; cavitation; microbubble; low-intensity focused ultrasound

摘要："Immune checkpoint blockade (ICB) typified by anti-PD-1/PD-L1 antibodies as a revolutionary treatment for solid malignancies has been limited to a subset of patients due to poor immunogenicity and inadequate T cell infiltration. Unfortunately, no effective strategies combined with ICB therapy are available to overcome low therapeutic efficiency and severe side effects. Ultrasound-targeted microbubble destruction (UTMD) is an effective and safe technique holding the promise to decrease tumor blood perfusion and activate anti-tumor immune response based on the cavitation effect. Herein, we demonstrated a novel combinatorial therapeutic modality combining low-intensity focused ultrasound-targeted microbubble destruction (LIFU-TMD) with PD-L1 blockade. LIFU-TMD caused the rupture of abnormal blood vessels to deplete tumor blood perfusion and induced the tumor microenvironment (TME) transformation to sensitize anti-PD-L1 immunotherapy, which markedly inhibited 4T1 breast cancer's growth in mice. We discovered immunogenic cell death (ICD) in a portion of cells induced by the cavitation effect from LIFU-TMD, characterized by the increased expression of calreticulin (CRT) on the tumor cell surface. Additionally, flow cytometry revealed substantially higher levels of dendritic cells (DCs) and CD8(+) T cells in draining lymph nodes and tumor tissue, as induced by pro-inflammatory molecules like IL-12 and TNF-a. These suggest that LIFU-TMD as a simple, effective, and safe treatment option provides a clinically translatable strategy for enhancing ICB therapy."

基金机构：National Natural Science Foundation Project [82272025]; Venture and Innovation Support Program for Chongqing Overseas Returnees [cx2019027]; Chongqing Natural Science Foundation [cstc2021jcyj-msxmX0220]

基金资助正文："This research was funded by the National Natural Science Foundation Project (82272025), Venture and Innovation Support Program for Chongqing Overseas Returnees (cx2019027), and Chongqing Natural Science Foundation project (cstc2021jcyj-msxmX0220)."