Low TCR Binding Strength Results in Increased Progenitor-like CD8+ Tumor-Infiltrating Lymphocytes

Area of Science:

• Immunology
• Cancer Biology
• T-cell Biology

Background:

• T-cell receptor (TCR) binding strength to peptide-MHC complexes critically impacts T-cell functions.
• Studying TCR affinity effects is complex due to the diverse T-cell repertoire against a single antigen.

Purpose of the Study:

• To investigate how TCR binding strength influences the protein and transcriptional profile of endogenous T-cells responding to tumor-associated antigens (TAAs) within the tumor microenvironment (TME).
• To elucidate the impact of TCR affinity on T-cell differentiation, exhaustion, and tumor control.

Main Methods:

• Utilized MHC-tetramer labeling (flow cytometry and sequencing) to assess TCR-peptide-MHC binding affinity.
• Employed single-cell RNA sequencing to analyze transcriptional profiles of tumor-infiltrating lymphocytes (TILs) based on TCR affinity.
• Validated findings using a TCR transgenic mouse model with a defined low-affinity TCR.

Main Results:

• High-affinity TILs showed a bias towards proliferating phenotypes and progressed faster to T-cell exhaustion, correlating with better tumor control.
• Low-affinity TILs were enriched in progenitor-like phenotypes.
• TCR transgenic mice with low-affinity TCRs exhibited impaired tumor control and maintained a progenitor-exhausted phenotype.

Conclusions:

• High-affinity TCR interactions expedite T-cell fate decisions and differentiation compared to low-affinity interactions.
• TCR affinity dictates divergent forms of T-cell dysfunction, influencing TIL therapies and antitumor immunity.
• Understanding TCR affinity is crucial for optimizing T-cell-based cancer immunotherapies.