HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression

Abstract

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.

Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer

“…A trio of WFDC genes, consisting of HE4, SLPI, and elafin, is certified to play roles in the aggressiveness of OC ( 45 ). Among the mentioned WFDC genes, HE4 shortens the survival time by altering the tumor immune microenvironment ( 46 ), and researchers have found a linear correlation between HE4 level and the peripheral monocyte/lymphocyte ratio, which could predict the survival of OC patients ( 47 ). SLPI could silence the neutrophil elastase’s anti-tumor effects, which are immune-related capabilities of attenuating tumorigenesis and attacking distant metastasis ( 48 ).…”

Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure

“…WFDC2 (also known as HE4) suppresses osteopontin and promotes cell survival in an osteopontin‐ and interferon‐γ‐dependent manner 35 . WFDC2 is also linked to increased ARG1 activity and immune suppression 36 …”

Malignancy Assessment Using Gene Identification in Captured Cells Algorithm for the Prediction of Malignancy in Women With a Pelvic Mass

“…The inclusion of the WFDC-2 gene, which produces the protein HE4, is of interest as HE4 has recently been shown to play an inhibitory role of CD8 + infiltrating lymphocytes and inducing macrophages to the M2 nonactive form in the ovarian cancer tumor microenvironment. 48 Approximately 80% of epithelial ovarian cancers overexpress the HE4 protein, which may speak to the importance of the WFCD-2 gene in pathogenesis.…”