3.2.2. Humanized Murine Model

The use of human CDX and PDX models are severely limited when investigating the dynamic interplay between the tumor, tumor microenvironment, and immune system while studying human PDACs. To compensate for this, researchers have developed humanized murine models, where mice are engineered to express components of the human immune system [92,93]. Humanized mice were created by establishing mutations in the IL2 receptor common chain (IL2rgnull) in the non-obese diabetic (NOD)/SCID background [94,95]. With the combined lack of NK cell activity from the NOD background and the impaired B and T cell response from the SCID background, this model can support the implantation of human tissue, peripheral blood mononuclear cells (PBMCs) and hematopoietic stem cells (HSCs), allowing for the modeling of human adaptive immunity in immunocompetent mice [93,96]. It is important to note that, although these models allow for studies involving the adaptive immune system, these mice do not have the complete human immune system. This model

has shortcomings such as limited lymph node development, HLA incompatibility between grafted human immune components and PDAC cells/tissue, and limited ability to mimic human immune cell trafficking [97]. Traditionally, human PDAC is characterized as nonimmunogenic or "cold" tumors due to its lack of T-cell infiltration and immunosuppressive microenvironment [98]. However, tumor implantations in humanized murine models can cause T-cell infiltrations due to lack of histocompatibility, therefore changing classical cold tumors into artificially hot tumors, which can subsequently lead to false-positive results in immunotherapeutic investigations. Some studies have utilized the humanized murine model to try and better understand the role of the adaptive immune system and its role in anti-tumor immunity in the context of OV therapy [99]. While these studies may offer some insights into the role of anti-tumor immunity during OV therapy, there are many caveats to this model that still need to be addressed.
