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.
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.