Intrinsic STING expression inversely associates with survival in ovarian cancer patients

Abstract

<h3>Objectives:</h3> The DNA sensing cGAS-STING signaling pathway plays a dual role of anti-tumor immunity and tumorigenesis. Chemoradiotherapy and PARPi induce DNA damage leading to activation of the cGAS-STING pathway, robust anti-tumor responses and improved clinical outcomes. Chronic activation of STING signaling creates an immunosuppressive TME and promotes metastases. Studies show that ovarian cancer cells have defective STING signaling. Current therapeutic strategies are focused on harnessing the beneficial effects of PARPi, IC blockade and STING agonists. However, the role for intrinsic ovarian tumor cGAS-STING levels in treatment responses and patient survival is unknown. The goal of this study is to determine the effect of tumor-specific cGAS-STING expression on survival in ovarian cancer patients. <h3>Methods:</h3> Using the Roswell Park Cancer Registry (RPCR), TMAs were generated from 488 patients treated for ovarian, fallopian tube or primary peritoneal cancer from 1991-2012. TMAs were stained for cGAS, STING and CD8 by IHC. cGAS and STING were scored based on the staining intensity (0-3) and the percent of positive cells (0-3) with a maximum combined score of 6 (0=no expression, 6=strong staining in >50% of cells). Additionally, the OS, PFS and cGAS-STING expression in 558 ovarian cancer patients from TCGA were analyzed. Clinico-pathologic data (age, demographics, histopathology, stage, tumor grade, treatment response, recurrence and survival) were retrieved from the electronic health records. <h3>Results:</h3> TCGA ovarian cancer patients with tumors expressing cGAShighSTINGhigh compared to cGASlowSTINGlow had OS of 38.4 months vs. 31.18 months (p=0.05). There was a significant positive correlation between gene and protein expression for cGAS (r=0.39, p=0.01) and STING (r=0.62, p<0.0001). Of the 488 patients in the RPCR, 95.3% were Caucasian with a median age at diagnosis of 63 years (range 20-93) and a median follow up of 44 months (range 0-279). The majority were diagnosed at an advanced surgical stage (68% and 14% at stage III and IV respectively), serous histology in 72% and high grade in 90.6% of cases. 72% received optimal and 27% had suboptimal debulking surgery. All patients received adjuvant platinum and taxane chemotherapy and the initial recurrence rate was 52%. In addition, 42.2% were platinum sensitive, 30% were refractory and 18% were platinum resistant. During the first 60 months of follow up, there was a trend toward improved OS and PFS in patients with cGASlowSTINGlow compared to cGAShighSTINGhigh tumors. Independently, cGAS did not associate with OS or PFS. Interestingly, STING high tumors correlated positively with CD8+ TILs (r=0.05, p=0.0002) but associated with decreased PFS (p=0.016). <h3>Conclusions:</h3> TCGA dataset revealed cGAShighSTINGhigh expressing tumors correlated with improved OS. By contrast, high grade ovarian tumors with intrinsically high levels of STING correlate with increased CD8+ TILs and decreased PFS.