Sofya Marchenko

Transcriptome Analysis of Matched Cohorts of Long- and Short-term Survivors in Advanced High-grade Serous Tubo-ovarian Cancer

Abstract Purpose: The late-stage diagnosis and the aggressiveness of high-grade serous tubo-ovarian carcinoma (HGSC) often result in poor survival outcomes, yet some patients exhibit an exceptionally long survival rate. This study aimed to identify molecular profiles associated with long-/short-term survival in HGSC, with the goal of better understanding protective factors and developing new treatments. Experimental Design: To discover molecular drivers causing the aggressiveness of HGSC, tumor samples from 12 long-term HGSC survivors (>7 years overall survival) and 12 short-term survivors (<1 year overall survival) were analyzed using targeted RNA sequencing followed by computational analysis. We investigated differentially expressed genes and their functional relevance, inferred differences in cell type composition and signaling pathways, as well as mutation status. To validate our findings, we simulated our study design by using HGSC The Cancer Genome Atlas dataset samples. We evaluated differential patterns of gene expression between these two groups and developed molecular profiles of HGSC that correlate with survival phenotypes. Results: Besides known molecular cancer drivers and indicators of poor prognosis, we identified specific transcriptional changes between short- and long-term survivors of HGSC, which indicate that immune processes play a fundamental role in long-term survivors. Our computational analysis reveals an important role for the ensemble of IFN-γ signaling and the RFX transcription factors, as well as the immune cell composition of the tumor microenvironment. Conclusions: Specific immunologic requirements involving IFN-γ signaling and affected pathways seem to be relevant for long-term survival in the generally considered nonimmunogenic HGSC, necessitating further research to improve diagnostic strategies and targeted therapies.

Increased expression of IDO1 is associated with improved survival and increased number of TILs in patients with high-grade serous ovarian cancer

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltrating lymphocytes (TILs) in HGSOC. Immunohistochemical (IHC) staining and bioimage analysis using the QuPath software were employed to assess IDO1 protein expression in a well-characterized cohort of 507 patients with primary HGSOC. Statistical evaluation was performed using SPSS, and in silico validation considering IDO1 mRNA expression in bulk and single-cell gene expression datasets was conducted. Additionally, IDO1 expression in interferon-gamma (IFNG) stimulated HGSOC cell lines was analyzed. Our findings revealed that IDO1 protein and mRNA expression serve as positive prognostic markers for overall survival (OS) and progression-free survival (PFS) in HGSOC. High IDO1 expression was associated with a significant improvement in OS by 21 months (p < 0.001) and PFS by 6 months (p = 0.016). Notably, elevated IDO1 expression correlated with an increased number of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ TILs (p < 0.001). Furthermore, high IDO1 mRNA expression and protein level were found to be associated with enhanced responsiveness to pro-inflammatory cytokines, particularly IFNG. Our study provides evidence that IDO1 expression serves as a positive prognostic marker in HGSOC and is associated with an increased number of CD3+, CD4+ and CD8+ TILs. Understanding the intricate relationship between IDO1, TILs, and the tumor microenvironment may hold the key to improving outcomes in HGSOC.