Abstract B054: TGFBI modulates immune cell infiltration in ovarian cancer and represents a potential therapeutic target

Abstract Ovarian cancer (OvCa) is the fifth leading cause of cancer-related deaths among women, with a 5-year survival rate of 25–30%. OvCa infiltration by cytotoxic CD8+ T cells correlates with improved clinical outcomes suggesting an important role for the immune system in controlling cancer growth. Unfortunately, T cells are commonly restricted to peritumoral stroma (tumor immune exclusion) limiting their benefit. We recently found that tumor immune exclusion is driven by cancer-associated mesenchymal stem cells (CA-MSCs). CA-MSCs express high levels of TGFBI (Transforming Growth Factor Beta-Induced), a secreted factor implicated in immune modulation and extracellular matrix remodeling. Despite growing evidence of its immunoregulatory functions, the role of TGFBI in shaping the ovarian tumor immune microenvironment remains poorly understood. We hypothesized that TGFBI modulates immune cell infiltration in OvCa and contributes to immune suppression. To investigate TGFBI function, female C57BL/6 wild-type (WT) and TGFBI knockout (KO) mice (10–12 weeks old) were subcutaneously injected with the immune hot UPK10 Ova^T-low ovarian cancer cells. UPK10 tumors grown in TGFBI-deficient mice showed a significant (∼5-fold)) restriction in tumor growth compared to tumors grown in WT controls. Notably, tumors in KO mice were significantly enriched in CD3ε+ and CD8+ T cells at day 18. A significant increase in CD3ε+, CD4+, CD8+ T cells, NKT cells were found in tumors in KO mice after 30 days of inoculation. In contrast, tumors in KO mice demonstrated a significant reduction in Ly6G+ cells. These findings were corroborated by multispectral IF. To better understand the role of MSC production of TGFBI in this immune modulation, in a parallel experiment, adipose-derived MSCs (WT or TGFBi-KO) were co-injected with tumor cells in wild type mice. In the MSC co-injection model, while overall tumor volumes did not differ significantly, KO-MSC–bearing mice had comparatively smaller tumors. Tumor analysis showed that tumors grown with KO-MSC compared to controls had increased infiltration of CD3ε+, CD4+, NK1.1+, and mature NK (CD11b+CD27-) cells, along with CD4+ and CD8+ TCRγδ+ T cells, NKT cells, and CD107a+ NK cells. Combined, our data demonstrate that TGFBI plays a pivotal role in modulating immune cell infiltration in the ovarian tumor microenvironment, particularly affecting T cell, NK cell, and neutrophil populations. These findings establish TGFBI as a novel regulator of immune exclusion and a promising immunomodulatory target in ovarian cancer. Citation Format: Md Habibul H. Mazumder, Sandra Cascio, Ronald J. Buckanovich. TGFBI modulates immune cell infiltration in ovarian cancer and represents a potential therapeutic target [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B054.