The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval.

Purpose: Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is effective, but most patients develop chemo-resistant disease. Mechanisms driving clinical chemo-response or -resistance are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant chemotherapy (NACT). NACT offers a window to profile pre- versus post-NACT tumors, which we used to identify chemotherapy-induced changes to the tumor microenvironment. Experimental Design: We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (756 genes/14 housekeeping genes) (NanoString), and performed reverse phase protein array on a subset of matched tumors. We examined cytokine levels in pre-NACT ascites samples (n=39) by enzyme-linked immunosorbent assays. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, reverse phase protein array (RPPA), and cytokine data by multi-spectral immunohistochemistry. Results: The most upregulated gene post-NACT was IL6 (16.79-fold). RPPA data were concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString (n=12), RPPA (n=4), and cytokine (n=39) studies identified an activated inflammatory signaling network and induced IL6 and IER3 (Immediate Early Response 3) post-NACT, associated with poor chemo-response and time to recurrence. Conclusions: Multi-omic profiling of ovarian tumor samples pre- and post-NACT provides unique insight into chemo-induced changes to the tumor microenvironment. We identified a novel IL-6/IER3 signaling axis that may drive chemo-resistance and disease recurrence.