Pharmaceutical targeting Th2-mediated immunity enhances immunotherapy response in breast cancer

作者全名："Chen, Yuru; Sun, Jiazheng; Luo, Yachan; Liu, Jiazhou; Wang, Xiaoyu; Feng, Rui; Huang, Jing; Du, Huimin; Li, Qin; Tan, Jinxiang; Ren, Guosheng; Wang, Xiaoyi; Li, Hongzhong"

作者地址："[Chen, Yuru; Sun, Jiazheng; Liu, Jiazhou; Wang, Xiaoyu; Feng, Rui; Ren, Guosheng; Li, Hongzhong] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China; [Chen, Yuru; Sun, Jiazheng; Liu, Jiazhou; Wang, Xiaoyu; Feng, Rui; Tan, Jinxiang; Ren, Guosheng; Wang, Xiaoyi; Li, Hongzhong] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China; [Luo, Yachan] Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing 400016, Peoples R China; [Huang, Jing] Chongqing Med Univ, Affiliated Hosp 1, Dept Resp, Chongqing 400016, Peoples R China; [Du, Huimin] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing 400016, Peoples R China; [Li, Qin] Capital Med Univ, Beijing Friendship Hosp, Dept Oncol, Beijing 100050, Peoples R China"

通信作者："Li, HZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing, Peoples R China.; Wang, XY; Li, HZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400016, Peoples R China."

来源：JOURNAL OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000903414100002

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Th2 cell; Suplatast tosilate; Breast cancer; Immune checkpoint blockade; Immunotherapy

摘要："Background: Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic. Methods: Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival. Results: Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8(+) T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4(+) T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects. Conclusions: Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy."

基金机构："National Natural Science Foundation of China; Natural Science Foundation of Chongqing [82173166, 81472475, 82273282]; Chongqing medical scientific research project [cstc2021jcyj-msxmX0015, 2022NSCQ-MSX0825]; CQMU Program for Youth Innovation in Future Medicine [2021MSXM033]; [W0094]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (NO. 82173166, 81472475, and 82273282), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0015 and 2022NSCQ-MSX0825), Chongqing medical scientific research project (NO.2021MSXM033) and CQMU Program for Youth Innovation in Future Medicine (NO. W0094)."