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

Wu, Yushen1,2,7; Yi, Ziying1,3; Li, Jie1,9,10; Wei, Yuxian2; Feng, Rui1; Liu, Jiazhou1; Huang, Jiefeng1,2; Chen, Yuru1,2; Wang, Xiaoyu1,2; Sun, Jiazheng2; Yin, Xuedong2; Li, Yunhai2; Wan, Jingyuan2,4; Zhang, Li5; Huang, Jing6; Du, Huimin7; Wang, Xiaoyi2; Li, Qin8; Ren, Guoshen1,2; Li, Hongzhon1,2

2022

10.7150/thno.68972

Theranostics   Impact Factor & Quartile

1838-7640

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.

FGFR breast cancer fibroblast VCAM-1 immunotherapy

SCI

English

Others

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]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000807464800006

IVYSPRING INT PUBL

Web of Science

1.Chongqing Med Univ, Chongqing Key Lab Mol Oncol & Epigenet, Affiliated Hosp 1, Chongqing 400016, Peoples R China
2.Chongqing Med Univ, Dept Endocrine & Breast Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China
3.Chongqing Gen Hosp, Dept Breast & Thyroid Surg, Chongqing 401147, Peoples R China
4.Chongqing Med Univ Chongqing, Dept Pharmacol, Chongqing 400016, Peoples R China
5.Chongqing Med Univ Chongqing, Dept Pathophysiol, Chongqing 400016, Peoples R China
6.Chongqing Med Univ, Dept Resp, Affiliated Hosp 1, Chongqing 400016, Peoples R China
7.Chongqing Med Univ, Dept Oncol, Affiliated Hosp 1, Chongqing 400016, Peoples R China
8.Capital Med Univ Beijing, Beijing Friendship Hosp, Dept Oncol, Beijing 100050, Peoples R China
9.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Dermatol, Jinan, Peoples R China
10.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China

Wu, Yushen,Yi, Ziying,Li, Jie,et al. FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts[J]. Theranostics,2022,12(10).

Wu, Yushen.,Yi, Ziying.,Li, Jie.,Wei, Yuxian.,Feng, Rui.,...&Li, Hongzhon.(2022).FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts.Theranostics,12(10).

Wu, Yushen,et al."FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts".Theranostics 12.10(2022).