Structure-guided engineering of CD112 receptor variants for optimized immunotherapy
Srishti Singh1, Estefania Julia2, Parismita Kalita3
1Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33612, USA.
Summary
Immune checkpoint protein CD112 receptor (CD112R) suppresses immune cells. Engineering CD112R variants enhanced T cell activation against cancer, demonstrating a strategy for developing novel immunotherapies.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- CD112 receptor (CD112R), also known as PVRIG, is an immune checkpoint protein that inhibits T and NK cell activation.
- CD112R binds to tumor-expressed CD112 (Nectin-2) ligands, dampening anti-tumor immune responses.
Purpose of the Study:
- To determine the structure of the CD112-CD112R complex.
- To engineer enhanced CD112-targeting immunotherapy candidates based on structural insights.
Main Methods:
- Determined the 2.2 Å-resolution crystal structure of the CD112-CD112R complex.
- Utilized structural analysis to guide directed evolution for CD112R variants.
- Engineered chimeric antigen receptors (CARs) and T cell engagers (TCEs) incorporating CD112R variants.
Main Results:
- The crystal structure revealed a lock-and-key binding mode where CD112R disrupts CD112 homodimerization.
- Directed evolution yielded CD112R mutants with significantly increased expression and binding affinity.
- The high-affinity variant CD112RIVE acted as a potent soluble CD112 trap.
- Engineered CARs and TCEs showed enhanced T cell activation and killing of CD112+ triple-negative breast cancer (TNBC) cells.
Conclusions:
- Structural insights into the CD112-CD112R interaction enable efficient engineering of affinity-tuned biologics.
- This strategy holds promise for developing novel immunotherapies targeting CD112-expressing cancers.
- Enhanced CD112R variants improve T cell-mediated anti-cancer activity.
