Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros expression and function to maintain T cell homeostasis in murine PC.
Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.
Pancreatic Cancer (PC) is one of the most aggressive and deadliest types of cancer, and it is projected to be the second leading cause of cancer-related deaths in the U.S. by the year 2030. PC evades immune surveillance by disrupting the immune homeostasis of effector T cells (Teff). T cells homeostasis is critical for proper anti-tumor immune responses. Preliminary flow cytometry data revealed that murine pancreatic (Panc02) cancer cells produce inflammatory soluble factors and in addition, express Major Histocompatibility Complex class I (MHC-I) and Programmed Death Ligand 1 (PD-L1) and 2 (PD-L2). PD-L1/2 can bind to PD-1 receptors on Teff and induce apoptosis or anergy, dampening the anti-tumor immunity. Cytokine bead array and flow cytometry analysis of serum from peripheral blood from C57BL/6 mice injected with Panc02 cells (TB mice) showed a significant increase in inflammatory factors compared to Control (CTRL) mice. Additionally, Teff from splenocytes from TB mice showed significant reduction in Teff percentages compared to CTRL mice, in vitro. In this study, CD3+ cells from CTRL mice were co-incubated with Panc02 cells pre-treated with anti-PD-L1 antibody (ab) to evaluate the modulation of Teff and cytokines production, in vitro. Mice were inoculated with the Panc02 pre-treated cells with anti-PD-L1 ab, to evaluate the modulation of Teff and cytokines production, in vivo. The results from this project may lead to the identification of new immunotherapeutic strategies to stabilize Teff homeostasis and function that could increase anti-tumor immune responses and combat PC progression.
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