Harnessing tumor microenvironment reorganization to improve immunotherapy in pancreatic ductal adenocarcinoma

In recent years, intriguing discoveries have led to the exploitation of immunotherapy to fight cancer. However, various obstacles, such as the inability of treatment to reach tumor site, must be overcome especially for solid cancers. Remodeling the tumor stroma or the immune compartment is a potential strategy to improve immunotherapies efficacy. Pancreatic ductal adenocarcinoma (PDAC) can be considered as a prototype of immunologically “cold” tumor. This feature results in limitations by the immune system to recognize and attack the tumor. In further detail, the aim of this thesis is to explore the controversial role of PDAC microenvironment, empathizing stromal cells, matrix components and most importantly the immune compartment. Rearrangements of such components are exploited to improve the chimeric antigen receptor (CAR)-T immunotherapy efficacy. In the first study, by Xiao, Zebin et al, combination of CAR-Ts is exploited to firstly manipulate the stroma by targeting the fibroblast activating protein (FAP), followed by “conventional” Mesothelin-CAR-Ts. The different treatment combinations and 2-photon live microscopy images offer an overview of the stromal reshaping and the switch to an immunological “hot” environment. The second research, by Fan, Jiawei et al., targets TYRO3, AXL, MERTK (TAM) receptors on PDAC cells by CAR-Ts and proposes their possible role inside the immune landscape, exploiting different modified cell lines and two graft models, with a focus on the phenotype of human immune system exploiting grafted human cells. Finally, Bhattacharjee, Sonakshi et al explored the different cancer associated fibroblasts (CAF) subsets, demonstrating their anti- and pro-tumor role, especially in PDAC liver metastasis. Exploiting several depleted mouse models they demonstrated that complete depletion of collagen I-producing CAFs leads to worse prognosis, paving the way for possible specific immunotherapies. Conclusively, these findings suggest a promising future in PDAC therapies by manipulating its surrounding microenvironment.