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Identifying Potential Neoantigens for Cervical Cancer Immunotherapy Using Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer.

ABSTRACT: Cervical cancer (CC) is one of the most common gynecological malignant tumors. The 5-year survival rate remains poor for the advanced and metastatic cervical cancer for the lack of effective treatments. Immunotherapy plays an important role in clinical tumor therapy. Neoantigens derived from tumor-specific somatic mutations are prospective targets for immunotherapy. Hence, the identification of new targets is of great significance for the treatment of advanced and metastatic cervical cancer. In this study, we performed whole-exome sequencing in 70 samples, including 25 cervical intraepithelial neoplasia (CINs) with corresponding blood samples and 10 CCs along with paired adjacent tissues to identify genomic variations and to find the potential neoantigens for CC immunotherapy. Using systematic bioinformatics pipeline, we found that C>T transitions were in both CINs and CCs. In contrast, the number of somatic mutations in CCs was significantly higher than those in CINs (t-test, P = 6.60E-04). Meanwhile, mutational signatures analysis revealed that signature 6 was detected in CIN2, CIN3, and CC, but not in CIN1, while signature 2 was only observed in CCs. Furthermore, PIK3CA, ARHGAP5 and ADGRB1 were identified as potential driver genes in this report, of which ADGRB1 was firstly reported in CC. Based on the genomic variation profiling of CINs and CCs, we identified 2586 potential neoantigens in these patients, of which 45 neoantigens were found in three neoantigen-related databases (TSNAdb, IEDB, and CTDatabase). Our current findings lay a solid foundation for the study of the pathogenesis of CC and the development of neoantigen-targeted immunotherapeutic measures.

SUBMITTER: Bao C

PROVIDER: S-EPMC8249860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:SGN-00101 (HspE7, Nventa, San Diego, CA) is a novel therapeutic vaccine consisting of a fusion protein containing an M. bovis BCG heat shock protein (Hsp65) covalently linked to the entire sequence of HPV 16 E7. This trial was designed to evaluate the efficacy and toxicities of HspE7 in women with CIN III.HIV (-) women with biopsy-proven CIN III were eligible. Two cohorts were accrued; one cohort to establish efficacy and a second cohort with a longer follow-up period to improve the precision of the trial to estimate response rates. Each patient underwent 3 monthly subcutaneous vaccinations with 500 microg of HspE7 followed by monthly colposcopic follow-up for 1 month in cohort 1 and an extended observation period (2 months) in cohort 2. All patients then underwent a LEEP or cone biopsy of the cervix. A complete pathologic response (pCR) was defined as no evidence of CIN or CIN I (only HPV changes). A partial response (PR) was defined as colposcopic lesion regression of >50% in size. Cervicovaginal lavage samples were obtained at each visit for HPV typing using MY09/ MY11 HPV PCR.Seventy-two patients were registered and screened, of whom 64 were eligible. Fifty-eight patients completed the trial and were evaluable (31 in cohort 1, 27 in cohort 2). There were no significant epidemiologic or HPV type differences between the 2 cohorts so responses were combined for analysis. Of the 58 evaluable patients, 13 (22.5%) had a pCR; 32 (55%) had a PR and 11 (19%) had stable disease. Two (3.5%) patients in cohort 2 had microinvasive disease and were defined as progressive disease. Thirty-three of 58 (57%) of the patients were infected with HPV 16 prior to vaccination or in subsequent visits. There was no significant difference in regression in women infected with HPV 16 compared to those without HPV 16 infection (88% vs. 70%; p=0.12). Women who had a previous LEEP or ablation for CIN were 2.7 times more likely to have a complete response compared to patients without previous treatment, although the difference was not statistically significant (95% CI for rate ratio: 0.95-6.19, p=0.10). At a cellular level, there was a significant association between local inflammation and response; lower grade of lesional inflammation correlated with a response to HspE7 (p=0.04 using Wilcoxon rank sum test).HspE7 appeared to demonstrate activity in women with CIN III and met a priori assumptions for efficacy; however, it is unclear whether this response was due to natural regression rather than treatment effect. HspE7, which targets the HPV 16 E7 oncoprotein, had efficacy in patients infected with HPV types other than 16, suggesting cross-reactivity. A larger randomized, controlled trial is needed to better define efficacy and to identify subsets of women most likely to benefit from immunotherapy.

Project description:Cervical cancer remains one of the most prevalent cancers among females worldwide. Therefore, it is important to discover new biomarkers for early diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer, preferably non-invasive ones. In the present study, we aimed to identify unique metabolic signatures for CINs and cervical cancers using global and targeted metabolomic profiling. Plasma samples (69 normal, 55 CIN1, 42 CIN2/3, and 60 cervical cancer) were examined by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) coupled with multivariate statistical analysis. Metabolic pathways were analyzed using the integrated web-based tool MetaboAnalyst. A multivariate logistic regression analysis was conducted to evaluate the combined association of metabolites and human papillomavirus (HPV) status with the risk of cervical carcinogenesis. A total of 28 metabolites exhibiting discriminating levels among normal, CIN, and cervical cancer patients (Kruskal-Wallis test p < 0.05) were identified in the global profiling analysis. The pathway analysis showed significantly altered alanine, aspartate, and glutamate metabolic pathways (FDR p-value < 0.05) in both the discovery and validation phases. Seven metabolites (AMP, aspartate, glutamate, hypoxanthine, lactate, proline, and pyroglutamate) were discriminated between CINs and cervical cancer versus normal (area under the curve (AUC) value > 0.8). The levels of these metabolites were significantly high in patients versus normal (p < 0.0001) and were associated with increased risk of developing CIN2/3 and cervical cancer. Additionally, elevated levels of the seven metabolites combined with positive HPV status were correlated with substantial risk of cancer progression. These results demonstrated that metabolomics profiling is capable of distinguishing CINs and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis.

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Identifying Potential Neoantigens for Cervical Cancer Immunotherapy Using Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer.

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