Abstract 1689: Ovarian tumor-induced CISH expression is an immune checkpoint for NK cells

Background: Non-specificity of symptoms in early stages of ovarian cancer (OVCA), lack of an early detection test and inefficient chemotherapy regimens lead to frequent recurrence and high mortality rates. OVCA differs from other malignancies as it disseminates by diffusion in the peritoneal cavity. Local immune function is critical and NK cells provide a first line of defense against a developing tumor. Tumors escape NK cell recognition by cleaving off ligands (MICA/B) for NK cell receptors (NKG2D) from their surface. However, preventing the cleaving of ligands does not improve tumor recognition by NK cells to desired levels, suggesting the existence of an additional inhibitory mechanism. Cytokines, including IL-15, play important roles in the proliferation and activation of NK cells. Nevertheless, longstanding exposure to cytokines induces exhaustion of NK cells through expression of CISH (Cytokine-inducible SH2-containing protein). The goal of this study was to examine whether NK cells in ovarian tumors express CISH and whether CISH expression is associated with tumor progression. Materials and methods: This study was conducted in an exploratory design using normal ovaries from postmenopausal women (60-80 years old, n=10), malignant ovarian tumors at early and late stages (n=12 from each stage, 3 from each of 4 histological OVCA types). Localization of CISH-expressing NK cells and expression of GRP78, a marker of cellular stress, were examined by immunohistochemistry (IHC) using paraffin sections. Representative samples were used for immunoblotting (WB) and gene expression studies. Results: Intense staining for CISH was observed for NK cells with occasional staining of malignant cells. Compared with normal ovaries, the population of CISH-expressing NK cells was greater in OVCA at early stage and increased further at late stages. The population of CISH-expressing NK cells was higher in serous OVCA at early stage as compared to other histological types at early stages. However, significant differences were not observed in the population of CISH-expressing NK cells among different histological types of OVCA at late stages. Immunoblotting showed stronger bands at ~30kDa for CISH for malignant tumors at early and late stages. Expression of GRP78 was significantly greater in ovarian tumors as compared with normal ovaries and increased further in OVCA at late stages. These results suggest the presence of cellular stress in ovarian malignant tumors and in their microenvironment are conducive to express a marker of exhaustion (CISH) by NK cells, which may suppress their anti-tumor functions. Thus, CISH may be an immune checkpoint for NK cells. Conclusion: The results of this study suggest that ovarian tumor development and progression is associated with increased expression of CISH by malignant cells and NK cells. Tumor-induced CISH expression may be associated with decreased anti-tumor function of NK cells. Support: NIH CA187309 Citation Format: Amy K. Stasik, Aparna Yellapa, Pincas Bitterman, Sameer Sharma, Sanjib Basu, Animesh Barua. Ovarian tumor-induced CISH expression is an immune checkpoint for NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1689.