Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy arising from the fallopian tubes that has a high rate of chemoresistant recurrence and low five-year survival rate. The ovarian cancer biomarker HE4 is known to promote proliferation, metastasis, chemoresistance, and suppression of cytotoxic lymphocytes. In this study, we sought to examine the effects of HE4 on signaling within diverse cell types that compose the tumor microenvironment. HE4 was found to activate STAT3 signaling and promote upregulation of the pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. Moreover, HE4 promoted increases in tube formation in an in vitro model of angiogenesis, which was also dependent upon STAT3 signaling. Clinically, HE4 and IL8 levels positively correlated in ovarian cancer patient tissue. Furthermore, HE4 serum levels correlated with microvascular density in EOC tissue and inversely correlated with cytotoxic T cell infiltration, suggesting that HE4 may cause deregulated blood vessel formation and suppress proper T cell trafficking in tumors. Collectively, this study shows for the first time that HE4 has the ability to affect signaling events and gene expression in multiple cell types of the tumor microenvironment, which could contribute to angiogenesis and altered immunogenic responses in ovarian cancer.

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Objective To compare outcomes of patients undergoing continent or incontinent urinary diversion after pelvic exenteration for gynecologic malignancies. Methods Data on patients who underwent pelvic exenteration for gynecologic malignancies at The University of Texas MD Anderson Cancer Center between January 1993 and December 2010 were collected. A multivariate logistic regression model was used and statistical significance was P < 0.05. Results A total of 133 patients were included in this study. The mean age at exenteration was 47.6 (range, 30–73) years in the continent urinary diversion group and 57.2 (range, 27–86) years in the incontinent urinary diversion group (P < 0.0001). Forty-six patients (34.6%) had continent urinary diversion, and 87 patients (65.4%) had incontinent urinary diversion. The rates of postoperative complications in patients with continent and incontinent urinary diversion, respectively, were as follows: pyelonephritis, 32.6% versus 37.9% (P = 0.58); urinary stone formation, 34.8% versus 2.3% (P < 0.001); renal insufficiency, 4.4% versus 14.9% (P = 0.09); urostomy stricture, 13.0% versus 1.2% (P = 0.007); ureteral (anastomotic) leak, 4.4% versus 6.9% (P = 0.71); ureteral (anastomotic) stricture, 13.0% versus 23% (P = 0.25); fistula formation, 21.7% versus 19.5% (P = 0.82); and reoperation because of complications of urinary diversion, 6.5% versus 2.3% (P = 0.34). Among patients with continent urinary diversion, the incidence of incontinence was 28.3%, and 15.2% had difficulty with self-catheterization. Conclusion There were no differences in postoperative complications between patients with continent and incontinent conduits except that stone formation was more common in patients with continent conduits.

Ovarian cancer is a highly fatal malignancy characterized by early chemotherapy responsiveness but the eventual development of resistance. Immune targeting therapies are changing treatment paradigms for numerous cancer types but have had minimal success in ovarian cancer. Through retrospective patient sample analysis, we have determined that high human epididymis protein 4 (HE4) production correlates with multiple markers of immune suppression in ovarian cancer, including lower CD8+ T cell infiltration, higher PD-L1 expression, and an increase in the peripheral monocyte to lymphocyte ratio. To further understand the impact that HE4 has on the immune microenvironment in ovarian cancer, we injected rats with syngeneic HE4 high– and low–expressing cancer cells and analyzed the differences in their tumor and ascites immune milieu. We found that high tumoral HE4 expression promotes an ascites cytokine profile that is rich in myeloid-recruiting and differentiation factors, with an influx of M2 macrophages and increased arginase 1 production. Additionally, CTL activation is significantly reduced in the ascites fluid, and there is a trend toward lower CTL infiltration of the tumor, whereas NK cell recruitment to the ascites and tumor is also reduced. PD-L1 expression by tumor cells and macrophages is increased by HE4 through a novel posttranscriptional mechanism. Our data have identified HE4 as a mediator of tumor-immune suppression in ovarian cancer, highlighting this molecule as a potential therapeutic target for the treatment of this devastating disease.