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

Author

Listed:
  • Duk Ki Kim

    (Korea Advanced Institute of Science and Technology (KAIST)
    Institute for Basic Science (IBS)
    Seoul National University College of Medicine
    Seoul National University Medical Research Center)

  • 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)
    Institute for Basic Science (IBS))

  • Keehoon Jung

    (Seoul National University College of Medicine
    Seoul National University Medical Research Center)

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.

Suggested Citation

  • 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 & Keehoon Jung, 2022. "PD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33991-6
    DOI: 10.1038/s41467-022-33991-6
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    References listed on IDEAS

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