The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and is characterized by a unique tumor microenvironment (TME) consisting of an abundant stromal component. Many features contained with the PDAC stroma contribute to resistance to cytotoxic and immunotherapeutic regimens, as well as the propensity for this tumor to metastasize. At the cellular level, PDAC cells crosstalk with a complex mixture of non-neoplastic cell types including fibroblasts, endothelial cells, and immune cells. These intricate interactions fuel the progression and therapeutic resistance of this aggressive cancer. Moreover, data suggest the polarization of these cell types, in particular immune and fibroblast populations, dictate how PDAC tumors grow, metastasize, and respond to therapy. As a result, current research is focused on how to best target these populations to render tumors responsive to treatment. Herein, we summarize the cell populations implicated in providing a supporting role for the development and progression of PDAC. We focus on stromal fibroblasts and immune subsets that have been widely researched. We discuss factors which govern the phenotype of these populations and provide insight on how they have been targeted therapeutically. This review provides an overview of the tumor microenvironment and postulates that cellular and soluble factors within the microenvironment can be specifically targeted to improve patient outcomes.

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance. METHODS: Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). RESULTS: The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. CONCLUSIONS: Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.