Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis. A transcriptomic-based immune modeling analysis was employed to determine levels of 8 immune cell subsets, 10 immune escape genes, and 22 co-inhibitory/co-stimulatory molecules in 26 HGSOC tumors. Multidimensional immune profiling analysis revealed CTLA-4, LAG-3, and Tregs as predictive for improved progression-free survival (PFS). Furthermore, the co-stimulatory receptor ICOS was also found to be significantly increased in patients with a longer PFS and positively correlated with levels of CTLA-4, PD-1, and infiltration of immune cell subsets. Both ICOS and LAG-3 were found to be significantly associated with improved overall survival in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. Finally, PVRL2 was identified as the most highly expressed transcript in our analysis, with immunohistochemistry results confirming its overexpression in HGSOC samples compared to normal/benign. Results were corroborated by parallel analyses of TCGA data. Overall, this multidimensional immune modeling analysis uncovers important prognostic immune factors that improve our understanding of the unique immune microenvironment of ovarian cancer.
Highlights
Epithelial Ovarian Cancer (EOC), is the most lethal of all gynecological malignancies, with approximately 21,750 women diagnosed, and 13,940 deaths from the disease in the United States in 2020 [1]
Multidimensional immune profiling analysis revealed the combination of CTLA4, LAG-3, and Tregs was significantly higher in patients with improved patient prognosis (Figure 1)
Individual analyte assessment revealed that LAG-3, cytotoxic T lymphocyte-associated protein-4 (CTLA-4), ICOS, and TNFRSF18 transcripts were significantly more abundant in the long progression-free survival (PFS) group compared to the short (p < 0.05)
Summary
Epithelial Ovarian Cancer (EOC), is the most lethal of all gynecological malignancies, with approximately 21,750 women diagnosed, and 13,940 deaths from the disease in the United States in 2020 [1]. While melanoma and non-small cell lung cancer (NSCLC) patients have seen a great benefit from targeting immune checkpoint inhibitors such cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or programmed cell death protein 1 (PD-1), EOC patients have only exhibited response rates of 10–15% [3]. Despite these poor response rates, evidence suggests that EOC is an immunogenic cancer. While evidence suggests that EOC patients could benefit from some form of immunotherapy, further research is needed in order to improve response rates
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