Cargando…

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

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 ce...

Descripción completa

Detalles Bibliográficos
Autores principales: Høye, Eirik, Dagenborg, Vegar J, Torgunrud, Annette, Lund-Andersen, Christin, Fretland, Åsmund A, Lorenz, Susanne, Edwin, Bjørn, Hovig, Eivind, Fromm, Bastian, Inderberg, Else M, Greiff, Victor, Ree, Anne H, Flatmark, Kjersti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170408/
https://www.ncbi.nlm.nih.gov/pubmed/37161965
http://dx.doi.org/10.1093/gigascience/giad032
Descripción
Sumario: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.