PD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer

Duk Ki Kim, Juhee Jeong, Dong Sun Lee, Do Young Hyeon, Geon Woo Park, Suwan Jeon, Kyung Bun Lee, Jin-Young Jang, Daehee Hwang, Ho Min Kim () and Keehoon Jung ()
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Duk Ki Kim: Korea Advanced Institute of Science and Technology (KAIST)
Juhee Jeong: Seoul National University College of Medicine
Dong Sun Lee: Institute for Basic Science (IBS)
Do Young Hyeon: Seoul National University
Geon Woo Park: Seoul National University College of Medicine
Suwan Jeon: Seoul National University College of Medicine
Kyung Bun Lee: Seoul National University College of Medicine
Jin-Young Jang: Seoul National University College of Medicine
Daehee Hwang: Seoul National University
Ho Min Kim: Korea Advanced Institute of Science and Technology (KAIST)
Keehoon Jung: Seoul National University College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141+ CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.

Date: 2022
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DOI: 10.1038/s41467-022-33991-6

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