Abstract 918: Tumor-induced interleukin 16 (IL-16) is associated with suppression of antitumor functions of NK cells in ovarian cancer

Abstract Background: Natural Killer (NK) cells kill tumor cells directly and provide first line of defense against the development and progression of ovarian cancer (OVCA). OVCA progresses mainly through local diffusion by suppression of NK cells. Factors and mechanism(s) involved in tumor-induced NK suppression are unknown. Such information is critical to develop NK-targeted therapies and OVCA prevention as current immunotherapies including T-cell targeted ones show poor efficacies against OVCA. Ovarian and fimbrial tissues are persistently exposed to inflammation/stress due to ovulation or infection and accompanied with high expression of interleukin 16 (IL-16), a proinflammatory cytokine. IL-16 is suggested to be associated with malignant transformation and secretion of IL-15 by ovarian tumors. IL-16 may play a role in suppression of NK cells by exhausting them through persistent stimulation by IL-15, a stimulator of NK cells. The goal of this study was to examine if tumor-induced IL-16 is associated with suppression of NK cell functions during OVCA development and progression and if so, to determine the mechanism of IL-16-induced suppression of NK cell functions. Materials and Methods: Association of ovarian/fimbrial tumor-induced IL-16 expression with the suppression of anti-tumor functions of NK cells was examined in an exploratory study using laying hen model of spontaneous OVCA. Fimbrial and ovarian tissues from normal hens (n=10, 3-4 years old), hens with early (n = 8) and late stage OVCA (n = 10) were examined. Tissue expression of IL-16, GRP78 (glucose regulated protein 78, a marker of cellular stress), NK cells (CD56+), IL-10/IL-15 and CISH (a marker of NK cell exhaustion) were examined. Changes in the frequencies of immunopositive cells or intensities of their expression and association among them during OVCA development were determined. Data were analyzed by ANOVA and t-test and significance was taken when P<0.05. Results: Frequency of IL-16-expressing cells and intensities of GRP78 expression were significantly (P<0.001) increased during OVCA development. Frequency of NK cells in tumor stroma was significantly higher in hens with early and late stage OVCA than normal hens (P<0.001). IL-16 expression was positively correlated with IL-15 expression. However, frequency of intratumoral NK cells was not increased significantly in late stage than early stage OVCA suggesting that OVCA progresses with reduction in intratumoral influx of NK cells. It is possible that consistent exposure of NK cells to persistent high levels of tumor-induced IL-15 might be a reason. Conclusion: The results of this study suggest that enhanced IL-16 expression during malignant transformation may inhibit intra-tumoral influx of NK cells. Thus, tumor-induced IL-16 offers a potential target for immunotherapy to enhance anti-tumor functions of NK cells. Support: Ovarian Cancer SPORE, Roswell Park. Citation Format: Animesh Barua, James T. O'Donnell, Dale B. Hales, Janice M. Bahr. Tumor-induced interleukin 16 (IL-16) is associated with suppression of antitumor functions of NK cells in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 918.