T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: An exploratory proof-of-principle study.

Lang Kuhs KA, Lin SW, Hua X, Schiffman M, Burk RD, Rodriguez AC, Herrero R, Abnet CC, Freedman ND, Pinto LA, Hamm D, Robins H, Hildesheim A, Shi J, Safaeian M
PLoS One. 2018 13 (1): e0178167

PMID: 29385144 · PMCID: PMC5791954 · DOI:10.1371/journal.pone.0178167

BACKGROUND - It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer. We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16.

METHODS - TCR repertoires of women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n = 25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n = 51], D [n = 2], J [n = 13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status.

RESULTS - TCR repertoire richness was associated with CIN3+ status (P = 0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V-gene (TRBV6-7) was significantly associated with CIN3+ status (RA = 0.11%, 0.16%, among cases and controls, respectively, Bonferroni P = 0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90).

CONCLUSIONS - Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed.

IMPACT - This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection.

MeSH Terms (11)

Case-Control Studies Cervical Intraepithelial Neoplasia Cohort Studies Female Human papillomavirus 16 Humans Papillomavirus Infections Receptors, Antigen, T-Cell Reproducibility of Results Uterine Cervical Neoplasms VDJ Recombinases

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