Objective The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC). Design Humanised hCD34(+)/hCD3e(+), Trp53(R172H)Kras(G12D)Pdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted. Results CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64(+) cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-alpha-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosphorylation of VAV2 (Y172) in CD64(+) CAFs and weakened desmoplasia. Additionally, decreased cyclic guanosine-adenosine monophosphate synthase/stimulator of interferon genes (STING) activity reduced proliferation of TCF-1(+)PD-1(+) stem-like CD8(+) T cells, which limited late-stage effects of BiTEs. Finally, vilanterol and the STING agonist synergistically boosted the efficacy of BiTEs by inhibiting the activation of CD64(+) CAFs and enriching proliferation of stem-like CD8(+) T cells, resulting in sustained anti-tumour activity. Conclusion Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.
[1]Tianjin Med Univ Canc Inst & Hosp, Natl Key Lab Druggabil Evaluat & Systemat Translat, Tianjin Key Lab Digest Canc, Dept pancreat Canc,Tianjins Clin Res Ctr Canc,Natl, Tianjin, Peoples R China.
[2]Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Tianjins Clin Res Ctr Canc,Dept Clin Lab, Tianjin, Peoples R China.
[3]Chinese Acad Sci, Inst Chem, State Key Struct Chem Unstable & Stable Species, Beijing, Peoples R China.
[4]North China Univ Sci & Technol, Coll Chem Engn, Hebei Key Lab Med Ind Integrat Precis Med, Tangshan, Peoples R China.
[5]Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Sr Ward, Tianjin Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China.
[6]Fudan Univ, Shanghai Canc Ctr, Dept Breast Surg, Key Lab Breast Canc Shanghai, Shanghai, Peoples R China.
[7]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.
(8.0+极速模式)