STING pathway expression in low‐grade serous carcinoma of the ovary: an unexpected therapeutic opportunity?

Abstract

Ovarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype-specific treatment modalities, especially for women with widespread and chemo-resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS-STING pathway that mediates innate immune defence against infectious DNA-containing pathogens and also detects tumour-derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low-grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high-grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low-grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.

Low-Grade Serous Carcinoma of the Ovary: The Current Status

“…The STING pathway is suppressed through epigenetic silencing or loss of function mutations. While these data require further validation, the STING pathway could offer a prospect of therapeutic intervention [ 102 ].…”

Spatial tumor immune microenvironment phenotypes in ovarian cancer

“…In contrast, endometrioid tumors were indicated to have a stronger presence of Tregs (FOXP3 and CTLA-4), and tumor PD-L1 and IDO1 levels on par with HGSC. Interestingly, LGSC had high levels of STING, an immune stimulatory target which has been suggested an attractive therapeutic target in OC in general 32 , and has previously been shown to be highly expressed in LGSC in particular 33 . The small set of four clear cell tumors showed an overall weak immune response relative the other histotypes.…”

The emerging roles of TLR and cGAS signaling in tumorigenesis and progression of ovarian cancer

“…In OC, the expressional pattern of STING has been characterized across ovarian tumor histotypes. Huvila et al (2021) reported that STING expressed highly in low grade serous ovarian carcinoma and serous borderline tumors, heterogeneously expressed in high-grade serous and endometrioid carcinomas, but with low levels in clear cell and mucinous carcinomas. Such expression pattern of STING across OC subtypes may suggest differed functions of STING in different cellular origins of OC tumorigenesis.…”