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Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer

Long Qin1, Long Wang2, Junchang Zhang2

  • 1Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China.

Science Advances
|May 25, 2022
PubMed

Insights

Researchers identified urokinase-type plasminogen activator receptor (uPAR) as a promising target for diffuse-type gastric cancer (DGC). A novel anti-uPAR antibody, combined with PD-1 blockade, significantly inhibited tumor growth and improved survival in preclinical models.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Diffuse-type gastric cancer (DGC) presents challenges due to low HER2 positivity and resistance to standard therapies.
  • Current treatments for DGC, including chemotherapy and immune checkpoint inhibitors, show limited efficacy.
  • There is a critical need for novel therapeutic targets and strategies for DGC.

Purpose of the Study:

  • To identify and validate new therapeutic targets for diffuse-type gastric cancer.
  • To evaluate the efficacy of a novel anti-urokinase-type plasminogen activator receptor (uPAR) monoclonal antibody as a potential treatment for DGC.
  • To investigate the synergistic effects of anti-uPAR therapy combined with PD-1 blockade in DGC models.

Main Methods:

  • Development of a novel monoclonal antibody targeting domains II and III of uPAR.
  • Assessment of anti-uPAR antibody efficacy in combination with anti-Programmed cell death protein 1 (PD-1) therapy.
  • Utilized cell line-derived xenograft and patient-derived xenograft mouse models for in vivo studies.
  • Generated and tested uPAR chimeric antigen receptor (CAR)-T cells against DGC patient-derived organoids and in mouse models.

Main Results:

  • The novel anti-uPAR antibody effectively blocks urokinase-type plasminogen activator binding to uPAR.
  • Combination therapy of anti-uPAR and anti-PD-1 demonstrated significant inhibition of tumor growth and prolonged survival in preclinical DGC models.
  • uPAR CAR-T cells showed potent killing of DGC patient-derived organoids and provided survival benefits in established mouse models, particularly with PD-1 blockade.

Conclusions:

  • Urokinase-type plasminogen activator receptor (uPAR) is a viable therapeutic target for diffuse-type gastric cancer.
  • A novel anti-uPAR antibody, especially in combination with PD-1 blockade or as CAR-T cells, offers a promising new treatment strategy for DGC.
  • This study presents a unique approach to targeting uPAR for improved DGC therapy outcomes.

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