| Title: |
Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma |
| Authors: |
Loryn Holokai; Jayati Chakrabarti; Joanne Lundy; Daniel Croagh; Pritha Adhikary; Scott S. Richards; Chantal Woodson; Nina Steele; Robert Kuester; Aaron Scott; Mohammad Khreiss; Timothy Frankel; Juanita Merchant; Brendan J. Jenkins; Jiang Wang; Rachna T. Shroff; Syed A. Ahmad; Yana Zavros |
| Source: |
Cancers, Vol 12, Iss 3816, p 3816 (2020) |
| Publisher Information: |
MDPI AG |
| Publication Year: |
2020 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
pancreatic ductal adenocarcinoma (PDAC); myeloid derived suppressor cells (MDSCs); PD-L1; organoids; organoid/immune-cell co-culture; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; RC254-282 |
| Description: |
Purpose : Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method : Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results : Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions : Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.mdpi.com/2072-6694/12/12/3816; https://doaj.org/toc/2072-6694; https://doaj.org/article/bd17b6c52d204d0fb0a382175e98bdc8 |
| DOI: |
10.3390/cancers12123816 |
| Availability: |
https://doi.org/10.3390/cancers12123816; https://doaj.org/article/bd17b6c52d204d0fb0a382175e98bdc8 |
| Accession Number: |
edsbas.A8D59A31 |
| Database: |
BASE |