Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix
Yi Duan, Xiaozhen Zhang, Honggang Ying, Jian Xu, Hanshen Yang, Kang Sun, Lihong He, Muchun Li, Yongtao Ji, Tingbo Liang, Xueli Bai
Abstract
Abstract Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5 high CAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5 high CAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.