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Related Experiment Video

Updated: May 12, 2025

Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens
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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.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|April 26, 2025
PubMed
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.

Keywords:
CAR T cellsCD112CD112RT cell engagerscheckpoint blockadeimmunotherapyprotein engineeringstructural biology

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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.