Background: Tumor-induced immunosuppression may be a reason for aggressive metastasis of ovarian cancer (OVCA). OVCA is a fatal malignancy of women with the highest case to death ratio among gynecological cancers. Most of the OVCA patients are postmenopausal women affected severely by the toxicity of current chemotherapeutics and danger of radiotherapy. Thus immunotherapy may be an alternative option for OVCA patients. Because OVCA mainly disseminates in the peritoneal cavity, immune functions in the tumor environment plays a crucial role in its progression. However, the mechanism(s) of immunosuppression by ovarian tumors are not well understood. Expression of leukocyte inhibitory immunoglobulin-like transcript 3 (ILT3, a member of inhibitory receptor family) by the tumors is one of the mechanisms in tumor-induced immunosuppression. Prevention or blocking of ILT3 expression may enhance anti-tumor immune responses. Information on ILT3 expression in OVCA and its prevention is not available. Herbs have long been used in traditional medicine against many human diseases including cancers. Ashwagandha or Winter Cherry (ASH, Withania somnifera), a herb known for its anti-tumor property, may enhance anti-tumor immunity by reducing ILT3 expression.
Objectives: The goal of this study was to determine whether ovarian malignant tumors express ILT3 and whether dietary supplementation of ASH root powder reduces ILT3 expression in OVCA.
Methods: Two experiments were performed. In the first one, archived specimen from normal ovaries of postmenopausal women (n=10), benign tumors (cystadenomas/adenofibromas, n=10) and ovarian malignant tumors (papillary serous) at early (n=7) and late stages (n=10) were examined for ILT3 expression. In the second group, laying hens, a preclinical model of spontaneous OVCA, were used. Healthy hens with normal ovaries or hens with early stage OVCA (selected by transvaginal ultrasound scanning) were divided into 3 groups and provided with basal diet (control) or diet supplemented with either 1% or 2% ASH root powder for 90 days. Each group had 20 hens (15 healthy, 5 with early stage OVCA). Hens were euthanized thereafter and gross morphology including normal and tumor stages were recorded, serum, ovarian tissues with or without cancer were collected and processed for ILT3 expression by immunohistochemistry (IHC), Western blotting or gene expression analysis. Differences in ILT3 expression among different pathological or supplemented groups were analyzed by one-way ANOVA and paired t-test for group-wise comparison.
Results: Strong expression of ILT3 was detected in ovarian malignant tumors at early stage. A very weak or no expression of ILT3 was observed in normal ovaries, while it was weak to moderate for benign tumors. The expression was stronger as the OVCA progressed to late stages. Immunoblotting detected a band of approximately 55kDa. Similarities in the patterns of ILT3 expression was observed between OVCA hens and patients. As compared with untreated and 1% ASH-treated hens, tumor incidence and progression as well as ILT3 expression was decreased significantly in hens supplemented with 2% dietary ASH.
Conclusions: The present study suggests that ILT3 is expressed by ovarian papillary serous cancers, and the expression of ILT3 increases with the progression of OVCA to late stages. Dietary supplementation of OVCA hens with 2% ASH reduced ILT3 expression and decreased the rate of tumor progression. Decrease in tumor progression was associated with the decrease in ILT3 expression. Thus ILT3 represents a potential target for enhancing the anti-tumor immune function in OVCA patients.ASH may be used to reduce ILT3 expression and prevention of OVCA progression. Support: Swim across America.
Citation Format: Natasha Gupta, Sameer Sharma, Seby L. Edassery, Janice M. Bahr, Lindsey Franklin, Erika Paulsen, Pincas Bitterman, Animesh Barua. Association of leukocyte inhibitory immunoglobulin-like transcript 3 (ILT3) with ovarian cancer and prevention of its expression by dietary supplementation of Ashwagandha (Withania somnifera). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B061.
- ©2016 American Association for Cancer Research.