Abstract C02: Establishment of a human PDAC explant culture model for treatment prediction and characterization of the tumor microenvironment

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of death from cancer, with a 5-year survival of less than 8%. To date, the therapeutic approaches are chemotherapy regimens. Despite promising data from various preclinical models, new immunotherapeutic agents like checkpoint inhibitors (CPI), vaccines, oncolytic viruses, or TGFβ inhibitors do not show a benefit in the overall survival of patients. Thus, especially in PDAC and in respect to the immune system, there is an urgent need for sufficient preclinical systems that can mirror a human patient scenario. Therefore, we developed a human-based pipeline of whole explant tissue culture using PDAC to predict responses of the tumor to different types of treatments in a personalized manner. Material and Methods: Human cancer tissue is taken into culture after surgery for several days. We tested different timings and technical variations (e.g., thickness of explants, medium changing protocols) to find superior conditions for tissue viability. In culture, the explants can be treated with (pre-) clinical-grade drugs and subsequently processed for quality controls via evaluation of the tissue integrity (on H&E slides) and cytokine stability. Also, histologic analyzes (e.g., cancer cells, T cells, B cells, macrophages) as well as multiplex cytokine analyzes are carried out. This combined approach enables us to study the impact of various drugs on the tissue in terms of tumor cell death, changes in the infiltration and activation of lymphocytes and macrophage polarization, etc. Results In vivo features of the tissue and the matrix architecture as well as the cytokine signatures are well maintained in the explants. Our model is reproducible among different explants of the same tissue in terms of infiltrating cells and cytokine expression. In addition, we were able to achieve an overview of the cytokine signature of PDAC in patients and to distinguish between clusters of patients by identifying different immune landscapes, for example, immunologically hot and cold subtypes. Discussion: Our model is usable as a predictive system for the response of PDAC to different types of treatments and seems to be a reliable and sufficient preclinical extension alternative to mouse models, single-cell experiments, or organoid models. The whole context of the tissue is from human origin and we aim to expand our platform for multiscreening of drug responses for personalized decision-making. Furthermore, we described the tumor microenvironment in detail, unraveling the complex cytokine signature of PDAC, and subsequently identified different clusters of immune landscapes, which may be of prognostic value. Citation Format: Azaz Ahmed, Dyke Ferber, Meggy Suarez-Carmona, Bénédicte Lenoir, Rosa Klotz, Thilo Hackert, Nathalia Giese, Inka Zörnig, Dirk Jäger, Niels Halama. Establishment of a human PDAC explant culture model for treatment prediction and characterization of the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C02.