T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases

• Published in: Gigascience 2023
• Main Authors: Høye, Eirik, Dagenborg, Vegar Johansen, Kristensen, Annette Torgunrud, Lund-Andersen, Christin, Fretland, Åsmund Avdem, Lorenz, Susanne, Edwin, Bjørn von Gohren, Hovig, Eivind, Fromm, Bastian, Inderberg, Else Marit, Greiff, Victor, Ree, Anne Hansen, Flatmark, Kjersti
• Format: Article
• Language: Norwegian
• ISSN: 2047-217X; 2047-217X

Abstract Background Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T-cell infiltration in CLM using T-cell receptor (TCR) repertoire sequencing. Eighty-five resected CLMs from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T-cell fractions were calculated, repertoire clonality was analyzed based on Hill evenness curves, and TCR sequence convergence was assessed using network analysis. Results Increased T-cell fractions (10.6% vs. 6.3%) were detected in CLMs exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT-exposed tumors independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence. Conclusions TCR repertoire sequencing can be used to quantify T-cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T-cell clonal expansion in CLM in a clinical context.