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Abstract
Simple SummaryHigh-grade serous ovarian carcinoma (HGSC) could be analyzed with a molecular stratification defined by different genomic instability signatures associated with specific mutational process and prognostic biomarkers. Immune infiltrate is known to be a robust biomarker in HGSC. We aimed to investigate immune parameters according to genomic instability signatures. We observed that homologous recombination deficiency positive, copy cumber variant signature 7 and TCR (T cells receptor) clonality are good prognostic biomarkers in HGSC. Combining TCR clonality and genomic instability signature or T cell infiltration improved the prognostic value compared to each variable taken alone. We provided a description of immune parameters according to different genomic instability signatures. We identified TCR clonality, alone or combined with genomic instability, as a promising prognostic biomarker in HGSC.Purpose: Immune infiltration is a prognostic factor in high-grade serous ovarian carcinoma (HGSC) but immunotherapy efficacy is disappointing. Genomic instability is now used to guide the therapeutic value of PARP inhibitors. We aimed to investigate exome-derived parameters to assess the tumor microenvironment according to genomic instability profile. Methods: We used the HGSC TCGA (the cancer genome atlas) dataset with genomic characteristics, including homologous recombination deficiency (HRD), copy number variant (CNV) signatures, TCR (T cell receptor) clonality and abundance of tissue-infiltrating immune and stromal cell populations. We then investigated the relationship with survival data. Results: In 578 HGSC patients, HRD status, CNV signature 7 and TCR clonality were associated with longer survival. The combination of high CNV signature 7 expression and HRD status or high CNV signature 3 expression and high TCR clonality was associated with a trend towards longer survival compared to each variable alone. Combining T cell infiltrate and TCR clonality improved the prognostic value compared to T cells infiltration alone. Prognostic value of TCR clonality was confirmed in an independent cohort. Conclusions: TCR clonality is an emerging prognostic biomarker that improves T cell infiltrate information. Analysis of TCR clonality combined with genomic instability could be an interesting prognostic biomarker.
Highlights
Epithelial ovarian cancer represents the fifth leading cause of death from cancer among women
Five hundred and seventy-eight patients with High-grade serous ovarian cancer (HGSC) taken from the TCGA ovarian dataset were included in this analysis
Beyond T cell infiltrate, we investigated whether TCR clonality could have a prognostic value
Summary
Epithelial ovarian cancer represents the fifth leading cause of death from cancer among women. Despite the gold standard of debulking surgery and platinum/taxane-based chemotherapy, which results in initial response in approximately 75% of patients, most women with HGSC experience relapse and succumb to chemo-resistant disease [2]. Since 2020, maintenance therapy comprising an association of PARPi and bevacizumab is the recommended strategy for patients with a HRD profile [4]. Thereafter, immunotherapy using immune checkpoint inhibitors (ICI) targeting PD(L)-1 has been evaluated in ovarian cancer. Epithelial ovarian cancer is controlled by immune response, and high T cell infiltration is associated with better prognosis [10,11,12,13]. Despite the intrinsic prognostic role of immune infiltrates, most studies testing immunotherapy in HGSC patients failed to show a significant benefit, a small subset of patients seem to present response and prolonged survival [14,15,16]. Intense research activity is ongoing worldwide to identify predictive biomarkers of efficacy
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