Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors

• DOI: 10.3389/fimmu.2021.619209
• Publication Date: 2021-03-15T05:53:07Z
• Authors: Tinglei Huang; Fuli Li; Xiaojiao Cheng; Jianzheng Wang; Wenhui Zhang; Baiwen Zhang; Yao Tang; Qingli Li; Cong Zhou; Shuiping Tu
• Keywords: Immune checkpoint; Cancer Immunotherapy

Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In present study, a bone marrow-derived CAF (BMF) -rich model is successfully established by subcutaneously mixed inoculation BMFs and cells into mice BMF-mixed xenografts are demonstrated be resistant anti-PD-L1 antibody immunotherapy compared mere xenografts. vitro assays via co-culture system indicate that co-cultured induced overexpress PD-L1, while there no such phenomenon in cancer cells. The further knock-out PD-L1 rescues sensitivity therapy. Mechanistically, microarray assay, we identify upregulation stimulated medicated activation Wnt/β-catenin signaling pathway BMFs. Moreover, administration inhibitors, including XAV-939 Wnt-C59, distinctly inhibits expression combination significantly potentiates therapeutic outcome therapy tumors. summary, our study demonstrates Wnt inhibition augments efficacy overcoming BMF-mediated resistance.