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Targeted Molecular Construct for Bioorthogonal Theranostics of PD-L1-Expressing Cancer Cells
Shiao Y Chow1, Asier Unciti-Broceta1
1Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, U.K.
Abstract:
Molecular targeting of tumor-overexpressed oncoproteins can improve the selectivity and tolerability of anticancer therapies. The immunoinhibitory membrane protein programmed death ligand 1 (PD-L1) is highly expressed on certain tumor types, which masks malignant cells from T cell recognition and creates an optimal environment for the cancer to thrive and spread. We report here a ligand-tetrazine conjugate (LTzC) armed with a PD-L1 small molecule inhibitor to selectively target PD-L1-expressing cancer cells and inhibit PD-L1 function and conjugated to a tetrazine module and a lipoyl group to incorporate bioorthogonal reactivities and an oxidative stress enhancer into the construct. By pairing LTzC with an imaging probe, we have established a "track-&-tag" system for selective labeling of PD-L1 both on and in living cells using click chemistry. We have further shown the specificity and versatility of LTzC by click-to-release activation of prodrugs and selective killing of PD-L1-expressing breast cancer cells, offering a new multimodal approach to "track-&-treat" malignant cells that are capable of evading the immune system.
Insights
Researchers developed a novel ligand-tetrazine conjugate (LTzC) to target and inhibit PD-L1, a protein that helps cancers evade immune detection. This "track-&-treat" approach enables selective cancer cell labeling and killing, offering a new strategy for immunotherapy.
Area of Science:
- Oncology
- Immunology
- Chemical Biology
Background:
- Programmed death ligand 1 (PD-L1) is a key immune checkpoint protein highly expressed on various cancer cells.
- Tumor PD-L1 expression facilitates immune evasion by masking cancer cells from T cell recognition.
- Targeting PD-L1 offers a promising strategy to enhance anti-cancer immune responses.
Purpose of the Study:
- To develop a novel molecular construct for selective targeting and functional inhibition of PD-L1.
- To create a bioorthogonal "track-&-tag" system for visualizing PD-L1 in living cells.
- To demonstrate a multimodal "track-&-treat" approach for PD-L1-expressing cancers.
Main Methods:
- Synthesis of a ligand-tetrazine conjugate (LTzC) incorporating a PD-L1 inhibitor, bioorthogonal tetrazine, and lipoyl group.
- Utilizing click chemistry for selective labeling of PD-L1 with imaging probes.
- Demonstrating click-to-release activation of prodrugs and selective cancer cell killing.
Main Results:
- LTzC selectively targets and binds to PD-L1 on cancer cells.
- The "track-&-tag" system successfully labels PD-L1 in living cells via click chemistry.
- LTzC facilitates prodrug activation and selective elimination of PD-L1-positive breast cancer cells.
Conclusions:
- LTzC is a versatile tool for targeting PD-L1-expressing tumors.
- The developed system enables precise "track-&-tag" and "track-&-treat" functionalities.
- This multimodal approach holds potential for improving cancer immunotherapy by overcoming immune evasion.
