Organoid-Based Model for Personalized Treatment of Pancreatic Ductal Adenocarcinoma
Chantal Woodson, Loryn Holokai, Dr. Jayati Chakrabarti, Dr. Jiang Wang, Dr. Syed Ahmad, Dr. Yana Zavros
University of Cincinnati College of Medicine
Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) has a survival rate of only 8.5%. Resistant tumors show increased PD-L1 expression inducing cessation of anti-tumor activity in cytotoxic T Cells (CTLs). The mechanism by which PD-L1+ PDAC tumors evade the immune response is not well understood. Myeloid cells (MDSCs) block anti-tumor CTL response partially by activating the PD-L1 checkpoint on CTLs. Depleting the MDSC population enables an endogenous anti-tumor CTL response in PDAC patients.
Hypothesis: 1) Organoids derived from resected PDAC tumors provide an in vitro model for predicting personalized therapy. 2) Chemoresistant PD-L1+ organoids are sensitive to combinatorial therapy involving both checkpoint inhibition and MDSC depletion.
Methods: Organoids were generated from resected PDAC patient tumors. Autologous CTLs were isolated from whole blood of patients. Monocytes and dendritic cells were differentiated from Peripheral Blood Mononuclear Cells. HLA-DR+ dendritic cells isolated by FACS were co-cultured with CTLs to activate them against autologous PDAC tumor. Activated CTLs and/or MDSCs were co-cultured with organoids derived from the same PDAC tumor. Flow cytometry measured organoid PD-L1 expression and CTL proliferation in response to standard-of-care chemotherapy alone or in combination with checkpoint inhibition and/or MDSC depletion.
Results: 1) Patients that exhibited chemoresistance showed increased G-MDSC infiltration within their tumor tissue. 2) In an autologous organoid/CTL co-culture derived from a chemoresistant patient with elevated G-MDSC infiltration, approximately 50% PD-L1+ organoid cell death was observed when cultures were treated with either PD-1 inhibitor (PD-1I, Nivolumab) alone or in combination with chemotherapy. Importantly, the inclusion of G-MDSCs in the organoid/CTL co-culture hindered the efficacy of checkpoint inhibition by PD-1I. Depleting the co-culture of MDSCs using Cabozantinib maximized the efficacy of checkpoint inhibition in combination with chemotherapy to induce cancer organoid death. 3) Organoid/CTL co-cultures generated from chemo-naive patients were used to predict the efficacy of combinatorial therapy for these individuals.
Conclusions: Depletion of MDSCs within the PDAC tumor microenvironment may enable the CTL anti-tumor response. Thus, patient-derived organoid/immune cell co-cultures provide an approach to predict efficacy of combinatorial therapy and improve PDAC patient outcome.