Preexisting TCR Clones Drive Major Pathologic Responses in Patients with HNSCC Treated with Dual Immune Checkpoint...

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Immune checkpoint inhibitors (ICI) show variable efficacy in head and neck squamous cell carcinoma (HNSCC).
• Mechanisms underlying major pathological responses (MPR) to ICI in HNSCC are not well understood.
• Understanding CD8 T-cell dynamics is crucial for predicting treatment outcomes.

Purpose of the Study:

• To investigate longitudinal CD8 T-cell repertoire evolution in HNSCC patients treated with neoadjuvant ICI.
• To identify determinants of MPR in HNSCC.
• To evaluate the role of T-cell adaptivity and functional reprogramming in treatment response.

Main Methods:

• Single-cell TCR sequencing of paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs).
• Analysis of HNSCC patients receiving neoadjuvant anti-PD-1 with anti-CTLA-4 or anti-LAG-3.
• Development and application of the TCR Adaptivity Index (TAI) and Tumor Reactive Signature (TRS) score.

Main Results:

• Post-treatment CD8 T-cell pools were dominated by pre-existing clones, refuting the 'clonal replacement' hypothesis.
• MPR was associated with higher abundance and expansion of 'super-expanded' CD8 T-cell clones.
• The TAI, quantifying clonal flux, was the strongest predictor of MPR, correlating with functional reprogramming and tumor reactivity (TRS).

Conclusions:

• Dual ICI therapy induces MPR via adaptivity and functional reprogramming of pre-existing T-cell immunity.
• Successful HNSCC treatment requires coordinated T-cell repertoire response and functional maturation.
• A TRS-integrated TAI offers a framework for predicting ICI efficacy by combining clonal dynamics and functional reprogramming.