Tumour cells escape T cell-mediated immunosurveillance through the interaction between programmed death (PD-1) ligand 1 (PD-L1) on tumour cells and PD-1 on T cells. Strategies disturbing PD-1/PD-L1 have shown clinical advantages in various cancers. However, the limited response rate urges us to examine the molecular regulation of PD-L1.

In the recently published article from Nature Communications, by utilizing Bio X Cell’s anti-PD-L1 monoclonal antibody as one of the research tools, Ren, et al identified that trafficking protein particle complex subunit 4 (TRAPPC4) as a crucial PD-L1 regulator.

TRAPPC4 exhaustion accelerates a significant decline of PD-L1 expression in both in vivo and in vitro while overexpression of TRAPPC4 stimulates tumour cells to checkpoint therapy in murine tumour models, suggesting TRAPPC4 as a potential therapeutic target to enhance anti-tumour immunity.

Why PD-L1 expression is studied in this research?

  • The interaction between T-cell receptors (TCRs) on T cells and peptide-major histocompatibility complexes (MHCs) on target cells consists of a major part of T-cell-based immune elimination of tumours.
      • This process is harmonized mostly by several co-inhibitory and co-stimulatory ligands and their receptors, known as immune checkpoints.
  • Among these immune checkpoints, the programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis has turned up as an important therapeutic target in many malignancies.
      • Only a minority of patients show a long-lasting response to these therapies, and intrinsic resistance remains a difficult challenge.
      • One of the most common malignancies that are resistant to immune checkpoint blockade (ICB) is mismatch repair proficient colorectal cancer, which accounts for ~85% of cases of colorectal cancer.
  • Past studies demonstrated that PD-L1 expression on tumour cells, the tumour mutation burden and T-lymphocyte infiltration might be the key indicators of the clinical response.
      • PD-L1 expression status seems to be specifically important.

Role of TRAPPC4 in regulating PD-L1 and T-cell-mediated antitumor immunity

  • TRAPPC4 functions as a vesicular trafficking protein facilitating the endosomal recycling of PD-L1 to the cell membranes:
      • It interacts with PD-L1 and RAB11 marked recycling endosomes.
      • It acts as a scaffold for PD-L1 and RAB11 marked recycling endosomes.
      • It protects PD-L1 from being targeted for lysosomal degradation.
  • Suppressing of TRAPPC4 led to the sequential degradation of PD-L1 in lysosomes, hence diminishing the overall PD-L1 reserve in tumour cells and that on the cell surface.
  • The specific depletion of TRAPPC4 in tumour cells
    • Enhanced T-cell-mediated cytotoxicity toward tumour cells in vitro
    • Augmented antitumor immunity in vivo

Using Bio X Cell’s in-vivo antibodies as one of the research tools in cancer research

    • For this experiment, Ren, et al used an animal model and Bio X Cell’s anti-mouse PD-1 antibody as one of the research tools to investigate the role of TRAPPC4 in the regulation of PD-L1.
    • Overexpression of TRAPPC4 made mouse colon adenocarcinoma (MC38) tumours more susceptible to checkpoint blockade therapy, possibly due to the positive regulation of TRAPPC4 on the level of PD-L1.
    • The finding that TRAPPC4 overexpressed MC38 tumours were more sensitive to immune checkpoint blockade makes a potential case for TRAPPC4 as a therapeutic target and its potential to predict response to immune checkpoint blockade.

Read the full article here.

Reference:

1. Ren, Yimeng et al. “TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity.” Nature communications vol. 12,1 5405. 13 Sep. 2021, doi:10.1038/s41467-021-25662-9.

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