Ansofaxine hydrochloride inhibits tumor growth and enhances Anti-TNFR2 in murine colon cancer model

作者全名："Jing, Qianyu; Wan, Quan; Nie, Yujie; Luo, Junqian; Zhang, Xiangyan; Zhu, Lan; Gui, Huan; Li, Linzhao; Wang, Chenglv; Chen, Shuanghui; Wang, Mengjiao; Yuan, Haohua; Lv, Hang; Pan, Runsang; Jing, Qianjun; Nie, Yingjie"

作者地址："[Jing, Qianyu; Wan, Quan; Nie, Yingjie] Zunyi Med Univ, Sch Basic Med Sci, Zunyi, Peoples R China; [Nie, Yujie; Zhang, Xiangyan; Nie, Yingjie] Guizhou Prov Peoples Hosp, NHC Key Lab Pulm Immunol Dis, Guiyang, Peoples R China; [Luo, Junqian] First Peoples Hosp Jinzhong, Jinzhong, Peoples R China; [Zhu, Lan; Gui, Huan; Li, Linzhao; Wang, Chenglv; Chen, Shuanghui; Wang, Mengjiao; Yuan, Haohua; Lv, Hang] Guizhou Univ, Sch Med, Guiyang, Peoples R China; [Pan, Runsang] Guizhou Med Univ, Guiyang, Peoples R China; [Jing, Qianjun] Chongqing Med Univ, Chongqing, Peoples R China"

通信作者："Nie, YJ (通讯作者)，Zunyi Med Univ, Sch Basic Med Sci, Zunyi, Peoples R China.; Nie, YJ (通讯作者)，Guizhou Prov Peoples Hosp, NHC Key Lab Pulm Immunol Dis, Guiyang, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001131715700001

JCR分区：Q1

影响因子：4.4

年份：2023

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：ansofaxine hydrochloride; anti-TNFR2; exhausted CD8+T cells; Tregs; tumor immunotherapy; colon cancer

摘要："Introduction: As psychoneuroimmunology flourishes, there is compelling evidence that depression suppresses the anti-tumor immune response, promotes the progression of cancer, and inhibits the effectiveness of cancer immunotherapy. Recent studies have reported that antidepressants can not only alleviate the depressant condition of cancer patients, but also strengthen the anti-tumor immunity, thus suppressing tumors. Tumor necrosis factor receptor 2 (TNFR2) antagonistic antibodies (Anti-TNFR2) targeting tumor-infiltrating regulatory T cells (Tregs) has achieved great results in preclinical studies, and with a favorable toxicity profile than existing immunotherapies, and is expected to become a new generation of more effective treatment strategies. Understanding the effects of combination therapy with antidepressants and Anti-TNFR2 may help design new strategies for cancer immunotherapy.Methods: We treated CT26, HCT116, MCA38 and SW620 colon cancer cells with fluoxetine (0-50 mu M), ansofaxine hydrochloride (0-50 mu M) and amitifadine hydrochloride (0-150 mu M) to examine their effects on cell proliferation and apoptosis. We explored the antitumor effects of ansofaxine hydrochloride in combination with or without Anti-TNFR in subcutaneously transplanted CT26 cells in tumor-bearing mouse model. Antitumor effects were evaluated by tumor volume. NK cell, M1 macrophage cell, CD4+ T cell, CD8+ T cell, exhausted CD8+ T and regulatory T cell (Tregs) subtypes were measured by flow cytometry. 5-hydroxytryptamine, dopamine and norepinephrine levels were measured by ELISA.Results: Oral antidepression, ansofaxine hydrochloride, enhanced peripheral dopamine levels, promoted CD8+T cell proliferation, promoted intratumoral infiltration of M1 and NK cells, decreased the proportion of tumor-infiltrating exhausted CD8+T cells, and strengthened anti-tumor immunity, thereby inhibiting colon cancer growth. In combination therapy, oral administration of ansofaxine hydrochloride enhanced the efficacy of Anti-TNFR2, and produced long-term tumor control in with syngeneic colorectal tumor-bearing mice, which was attributable to the reduction in tumor-infiltrating Treg quantity and the recovery of CD8+ T cells function.Discussion: In summary, our data reveal the role of ansofaxine hydrochloride in modulating the anti-tumor immunity. Our results support that exhausted CD8+T is an important potential mechanism by which ansofaxine hydrochloride activates anti-tumor immunity and enhances anti-tumor effects of anti-TNFR2."

基金机构："National Natural Science Foundation of China [82060308]; National Key Laboratory of Respiratory Diseases [SKLRD-OP-202208]; Guizhou Provincial Science and Technology Projects [GPPH-NSFC-2020-6, GPPH-NSFC-2020-7]; Guizhou Immunotherapy Research Talent Base [2019PT320003]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [GCC [2022]037-1]; Ministry of Human Resources and Social Security of the People's Republic of China; [RCJD 2018-11]"

基金资助正文："The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82060308), National Key Laboratory of Respiratory Diseases (SKLRD-OP-202208), Guizhou Provincial Science and Technology Projects (GPPH-NSFC-2020-6; GPPH-NSFC-2020-7; GCC [2022]037-1), Guizhou Immunotherapy Research Talent Base (RCJD 2018-11), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320003) and funding from Ministry of Human Resources and Social Security of the People's Republic of China."