Circulating T-cell receptor repertoire for cancer early detection

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Liquid biopsy offers a non-invasive method for cancer diagnosis, but current circulating tumor DNA (ctDNA) detection has limitations for early-stage disease.
• Harnessing T-cell recognition through sequencing the circulating T-cell receptor (TCR) repertoire presents a novel strategy to enhance liquid biopsy sensitivity.

Purpose of the Study:

• To improve the sensitivity of liquid biopsy for early-stage lung cancer detection by analyzing the circulating TCR repertoire.
• To develop a cancer score based on TCR repertoire functional units (RFUs) and evaluate its performance against ctDNA and protein biomarkers.

Main Methods:

• Sequencing of the TCR β chain in 463 lung cancer patients (86% stage I) and 587 controls to identify TCR repertoire functional units (RFUs).
• Development of a support vector machine model using RFU frequencies to create a cancer score, evaluated via cross-validation.
• Comparison of the RFU cancer score with a ctDNA panel and cancer-related protein biomarkers.

Main Results:

• Identified 327 cancer-associated TCR RFUs, with 76% correlated with HLA alleles, suggesting antigen recognition.
• The RFU cancer score detected nearly 50% of stage I lung cancers at 80% specificity.
• Adding the RFU score to ctDNA and protein biomarkers boosted sensitivity by up to 20 percentage points.

Conclusions:

• Circulating TCR repertoire functional unit analysis is a valuable addition to liquid biopsy.
• This approach significantly complements established analytes, enhancing sensitivity for early-stage cancer detection.