Figure 11.

Proposed Model: (A) In the PC tumor microenvironment, tumor derived factors such as PC-induced miRNA-155 impacts hematopoietic stem cells (HSC) and alters myelopoiesis by targeting and downregulating SHIP-1 gene and protein expressions. The reduction in SHIP-1 expression corresponds with the expansion of M-MDSC that correspond with the development of pro-tumor M2-TAM which, in turn, impair anti-tumor immunity and result in PC progression and metastasis. (B) The therapeutic use of the bioflavonoid API induces apoptosis and necrosis of PC cells and causes a decrease in miRNA-155 in the pancreatic tumor. This reduction correlates with an increase in SHIP-1 gene and protein expressions that results in the expansion of M-MDSC which coincides with the development of tumoricidal M1-TAM. These tumoricidal M1-TAM have increased CD40 expression which interacts with CD40L on CD8⁺ T cells, resulting in M1-TAM activation, production of iNOS/NO and an overall increase in anti-tumor immunity. This is signified by the release of granzyme B (GrB) and perforin (PRF) as well as the robust activation of effector CD8⁺ T cells, leading to PC regression. Created with BioRender.com (accessed on 21 March 2022).