Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering

Area of Science:

• Immunology
• Biophysics
• Structural Biology

Background:

• T cells exhibit limited responsiveness to tumor self-antigens due to central tolerance, hindering effective tumor elimination.
• Developing T cell receptor (TCR) therapies requires overcoming this tolerance to target non-mutated tumor-associated antigens (TAAs).

Purpose of the Study:

• To engineer a T cell receptor (TCR) with enhanced reactivity against the tumor-associated antigen (TAA) prostatic acid phosphatase (PAP).
• To investigate the biophysical mechanisms underlying TCR-pMHC interactions and T cell activation.

Main Methods:

• Mechanical force was used to engineer a weakly reactive TCR specific for PAP.
• A "catch-bonding" hotspot mutation was introduced to increase TCR-peptide-major histocompatibility complex (pMHC) bond lifetime.
• Crystal structures and molecular dynamics simulations were employed to elucidate structural changes.
• T cell expansion, effector function, and tumor elimination were assessed in vivo.

Main Results:

• The engineered TCR demonstrated enhanced T cell activity by increasing TCR-pMHC bond lifetime while maintaining antigen specificity.
• T cells expressing the engineered TCRs exhibited superior expansion, enhanced effector phenotypes, and improved tumor elimination.
• Structural analysis revealed that a single amino acid mutation primes the TCR for peptide interaction via water reorganization at the TCR-pMHC interface.

Conclusions:

• Catch-bond engineering is a viable biophysically based strategy for enhancing T cell-mediated antitumor immunity.
• This approach can transform tolerized T cells into potent therapeutic agents for cancer treatment.
• The findings offer a novel strategy for developing effective TCR-T cell therapies against non-mutated TAAs.