Related Experiment Video
Updated: May 23, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor
Megan E Prosser1, Christine E Brown, Andrew F Shami
1Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Abstract:
Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted. As a strategy to overcome tumor PD-L1 effects on adoptively transferred T cells, we sought to convert PD-1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with that of CD28. Rather than becoming exhausted upon engagement of PD-L1(+) tumors, we hypothesized that CD8(+) cytotoxic T lymphocytes (CTL) genetically modified to express this PD1:CD28 chimera would exhibit enhanced functional attributes. Here we show that cell surface expressed PD1:CD28 retains the capacity to bind PD-L1 resulting in T cell costimulation as evidenced by increased levels of ERK phosphorylation, augmentation of cytokine secretion, increased proliferative capacity, and enhanced expression of effector molecule Granzyme B. We provide evidence that this chimera could serve as a novel engineering strategy to overcome PD-L1 mediated immunosuppression.
Insights
Scientists engineered a novel chimeric receptor to overcome tumor immune evasion. This PD1:CD28 chimera converts the inhibitory programmed death 1 (PD-1) into a costimulatory signal, enhancing T cell function against tumors expressing programmed death ligand 1 (PD-L1).
Area of Science:
- Immunology
- Cancer Biology
- Molecular Engineering
Background:
- Tumors evade immune detection by utilizing immune checkpoints, such as programmed death ligand 1 (PD-L1).
- PD-L1 expressed by tumors binds to programmed death 1 (PD-1) on T cells, leading to T cell exhaustion and immune suppression.
- This mechanism hinders the effectiveness of T cell-based immunotherapies, including adoptive T cell transfer.
Purpose of the Study:
- To engineer a novel chimeric receptor to counteract PD-L1-mediated immunosuppression.
- To convert the inhibitory PD-1 receptor into a costimulatory signal upon PD-L1 engagement.
- To enhance the anti-tumor function of genetically modified T cells in the presence of PD-L1.
Main Methods:
- Genetic engineering of cytotoxic T lymphocytes (CTLs) to express a chimeric receptor (PD1:CD28).
- The chimera replaces the transmembrane and cytoplasmic tail of PD-1 with that of CD28.
- Assessed T cell activation, proliferation, cytokine secretion, and effector molecule expression upon PD-L1 engagement.
Main Results:
- The PD1:CD28 chimera successfully binds to PD-L1 on tumor cells.
- Engagement of the chimera leads to T cell costimulation, evidenced by increased ERK phosphorylation.
- Enhanced T cell proliferation, cytokine secretion (e.g., Granzyme B), and functional attributes were observed.
Conclusions:
- The PD1:CD28 chimeric receptor effectively overcomes PD-L1-mediated immunosuppression.
- This engineered receptor converts an inhibitory signal into a costimulatory one, boosting T cell anti-tumor activity.
- This strategy offers a promising approach for enhancing adoptive T cell therapy efficacy against PD-L1(+) tumors.
Related Concept Videos
01:27Tumor Immunotherapy
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...