Murine-and human-derived autologous organoid/immune cell co-cultures as pre-clinical models of pancreatic ductal adenocarcinoma

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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number3816
Pages (from-to)1-25
Number of pages25
JournalCancers
Volume12
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Myeloid derived suppressor cells (MDSCs)
  • Organoid/immune-cell co-culture
  • Organoids
  • PD-L1
  • Pancreatic ductal adenocarcinoma (PDAC)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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