FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts

作者全名："Wu, Yushen; Yi, Ziying; Li, Jie; Wei, Yuxian; Feng, Rui; Liu, Jiazhou; Huang, Jiefeng; Chen, Yuru; Wang, Xiaoyu; Sun, Jiazheng; Yin, Xuedong; Li, Yunhai; Wan, Jingyuan; Zhang, Li; Huang, Jing; Du, Huimin; Wang, Xiaoyi; Li, Qin; Ren, Guoshen; Li, Hongzhong"

作者地址："[Wu, Yushen; Yi, Ziying; Li, Jie; Feng, Rui; Liu, Jiazhou; Huang, Jiefeng; Chen, Yuru; Wang, Xiaoyu; Ren, Guoshen; Li, Hongzhong] Chongqing Med Univ, Chongqing Key Lab Mol Oncol & Epigenet, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Wu, Yushen; Wei, Yuxian; Huang, Jiefeng; Chen, Yuru; Wang, Xiaoyu; Sun, Jiazheng; Yin, Xuedong; Li, Yunhai; Wan, Jingyuan; Wang, Xiaoyi; Ren, Guoshen; Li, Hongzhong] Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Yi, Ziying] Chongqing Gen Hosp, Dept Breast & Thyroid Surg, Chongqing 401147, Peoples R China; [Wan, Jingyuan] Chongqing Med Univ Chongqing, Dept Pharmacol, Chongqing 400016, Peoples R China; [Zhang, Li] Chongqing Med Univ Chongqing, Dept Pathophysiol, Chongqing 400016, Peoples R China; [Huang, Jing] Chongqing Med Univ, Dept Resp, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Wu, Yushen; Du, Huimin] Chongqing Med Univ, Dept Oncol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Li, Qin] Capital Med Univ Beijing, Beijing Friendship Hosp, Dept Oncol, Beijing 100050, Peoples R China; [Li, Jie] Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Dermatol, Jinan, Peoples R China; [Li, Jie] Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China"

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

来源：THERANOSTICS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000807464800006

JCR分区：Q1

影响因子：12.4

年份：2022

卷号：12

期号：10

开始页：4564

结束页：4580

文献类型：Article

关键词：FGFR; breast cancer; fibroblast; VCAM-1; immunotherapy

摘要："Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune ""cold"" tumor into ""hot"" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy."

基金机构："National Natural Science Foundation of China [82173166, 82101934, 81472475, 31420103915]; Natural Science Foundation of Chongqing [cstc2021jcyj-msxmX0015]; Chongqing medical scientific research project [2019MSXM019]; CQMU Program for Youth Innovation in Future Medicine [W0094]"

基金资助正文："Y.W., Z.Y., and J.L. contributed equally to this work. We thank Dr. Wenjing Wang for CyTOF analysis, and members of the Ren laboratory for helpful discussion. We thank the patients who donated samples and the Biobank, The First Affiliated Hospital of Chongqing Medical University for collection, annotation, and provision of clinical samples for the IHC/IF studies. This work was supported by the National Natural Science Foundation of China (No. 82173166, 82101934, 81472475, and 31420103915), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0015), the Chongqing medical scientific research project (No. 2019MSXM019) and CQMU Program for Youth Innovation in Future Medicine (NO.W0094)."