Abstract 4050: Immune microenvironment characteristics of primary tumor predict long-term disease-free survival in high-grade serous ovarian cancer (HGSOC)
Authors: Jones Wendell , Ganapathi Mahrukh , Michener Chad , Ganapathi Ram N. 
Published: August 2018

Epithelial ovarian cancer is a heterogeneous disease with HGSOC being the most common subtype and &gt;70% of women are diagnosed at an advanced stage of the disease. Standard of care involving primary cytoreductive surgery followed by first-line adjuvant platinum/taxane based chemotherapy can lead to a favorable response in 80% of the patients, but the rate of recurrence is &gt;70%. Patient outcome in serous ovarian cancer has been associated with presence of intra-tumoral T cells and an “immunoreactive” subtype. Further, chemotherapy can also affect the immune microenvironment in serous ovarian cancer. We hypothesized that in patients with HGSOC who have long-term disease-free survival the primary tumors harbor a more active adaptive immune cell response. To identify genes associated with immune activity we performed Pan-Cancer immunome analysis (Nature Methods 12, 453-457, 2015) of 4446 RNA-Seq tumor samples balanced for tissue and cancer subtypes, from The Cancer Genome Atlas (TCGA). This analysis yielded several highly correlated gene clusters. After mean-centering by gene and hierarchically clustering both genes and samples, gene-cancer type interactions as well as immunogenic tissue-independent characteristics in the clustered expression profile was observed. We identified a highly-correlated primary cluster of 57 genes associated with cytotoxic lymphocyte activity, referred to as the Cytotoxic Lymphocyte Immune Signature (CLIS). This signature was tested for association with disease-free survival (DFS) in a patient cohort (N=48) that received surgical cytoreduction of tumor followed by adjuvant platinum-taxane chemotherapy and was stratified in three risk-groups: a) Platinum-Resistant, median disease-free interval (MDFI) 0 months (range 0-12 months); b) Platinum-Sensitive, MDFI 15 months (range 13-30 months) and (c) Exceptional-Responders, MDFI &gt;80 months (range 66 - &gt;144 months). RNA isolated from frozen primary tumors was depleted of ribosomal RNA and sequenced using the Illumina TruSeq stranded Total Gold protocol yielding &gt;50M 100 bp paired-end sequences per specimen. In this patient cohort CLIS was distinct in &gt;66% of exceptional-responders compared to &lt;25% in platinum-resistant patients and 44% of platinum-sensitive patients. Using Cox proportional hazards regression, CLIS (p=0.0031), as well as M1 macrophage (p=0.020) and B-cell (p=0.028) signatures were independently associated with DFS after accounting for age and stage. This novel association between CLIS, M1 macrophage and B-cell signature in DFS was replicated independently in HGSOC patient datasets from TCGA, N=164 (p &lt; 0.05) and another (JNCI 106: dju249, 2014) HGSOC patient cohort, N=174 (p &lt; 0.05). In summary, primary tumors in exceptional responders with HGSOC harbor a distinct gene profile/immune microenvironment for optimal treatment efficacy.

Citation Format: Wendell Jones, Mahrukh Ganapathi, Chad Michener, Ram N. Ganapathi. Immune microenvironment characteristics of primary tumor predict long-term disease-free survival in high-grade serous ovarian cancer (HGSOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4050.