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TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity

Yimeng Ren1, Yun Qian1, Luoyan Ai1,2

  • 1State Key Laboratory for Oncogenes and Related Genes; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Nature Communications
|September 14, 2021
PubMed

Insights

Trafficking protein particle complex subunit 4 (TRAPPC4) regulates PD-L1 recycling on tumor cells. Inhibiting TRAPPC4 reduces PD-L1, enhancing T cell immunity and improving checkpoint therapy response.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumor cells evade immune surveillance through PD-1/PD-L1 interactions.
  • Disrupting PD-1/PD-L1 pathways offers clinical benefits but has limited response rates.
  • Understanding PD-L1 regulation is crucial for improving cancer immunotherapy.

Purpose of the Study:

  • To identify novel regulators of Programmed Death-1 Ligand 1 (PD-L1) expression.
  • To investigate the role of trafficking protein particle complex subunit 4 (TRAPPC4) in PD-L1 regulation.
  • To explore TRAPPC4 as a potential therapeutic target for enhancing anti-tumor immunity.

Main Methods:

  • Investigated TRAPPC4's interaction with PD-L1 in recycling endosomes.
  • Utilized TRAPPC4 depletion in vitro and in vivo models.
  • Assessed T cell-mediated cytotoxicity and response to checkpoint therapy in murine models.

Main Results:

  • TRAPPC4 acts as a scaffold, promoting RAB11-mediated recycling of PD-L1 to the tumor cell surface.
  • TRAPPC4 depletion significantly reduces PD-L1 expression.
  • Reduced PD-L1 enhances T cell-mediated cytotoxicity and sensitizes tumors to checkpoint therapy.

Conclusions:

  • TRAPPC4 is a key regulator of PD-L1 trafficking and surface expression.
  • Targeting TRAPPC4 can enhance the efficacy of current cancer immunotherapies.
  • TRAPPC4 represents a promising therapeutic target for overcoming resistance to checkpoint inhibitors.

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