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

Background It is unknown why a minority of women fail to clearhuman papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoiresmay 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 Studyto evaluate the utility of next-generation sequencing for interrogating the TCR repertoiresamong women who clearedand failed to clearcervical HPV16. Methods TCR repertoiresof women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who clearedan 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 repertoirerichness 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 repertoireamong women with CIN3+ compared to women who clearedinfection were observed. Impact This is the first study to use next-generation sequencing to investigate TCR repertoirein the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoiresfrom disease-free women who clearedHPV16 infection.