T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells

Area of Science:

• Immunology
• Cancer Therapy
• Molecular Biology

Background:

• T cell receptor (TCR) gene transfer offers potential for cancer immunotherapy by engineering patient T cells.
• Naturally occurring tumor-specific TCRs are often absent from the T cell repertoire due to thymic deletion of self-antigens.
• This limitation constrains the effectiveness of current T cell-based cancer therapies.

Purpose of the Study:

• To investigate the impact of T cell receptor (TCR) affinity on the functional properties of CD8(+) T cells targeting tumor antigens.
• To determine the existence and implications of affinity thresholds for T cell-mediated anti-cancer responses.
• To assess the potential for cross-reactivity with self-antigens when using engineered high-affinity TCRs.

Main Methods:

• Utilized altered peptide ligands and lentivirus-mediated transduction to introduce affinity-enhanced TCRs into T cells.
• Selected high-affinity TCRs specific for three distinct tumor-associated peptide antigens using phage display.
• Evaluated the functional characteristics of engineered CD8(+) T cells across a spectrum of TCR binding affinities.

Main Results:

• TCR affinity directly correlates with T cell antigen sensitivity and polyfunctionality.
• Identified supraphysiological affinity thresholds beyond which T cell function does not improve.
• Observed cross-reactivity with self-derived peptides in T cells expressing very high-affinity TCRs.

Conclusions:

• Optimizing TCR affinity within a defined window, exceeding natural TCR ranges, can enhance T cell effector functions.
• This approach allows for improved anti-tumor activity without compromising safety through off-target effects.
• Findings provide a basis for designing novel TCR-based biologics with improved preclinical validation for cancer treatment.