Abstract
Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation — multi-modal treatment approaches and exploitation of biologically integrated targets — which aim to remodel the TME against PDAC.
Key points
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Therapeutic approaches to target stromal desmoplasia, a histopathological hallmark of pancreatic ductal adenocarcinoma, have classically focused on depleting the stromal constituents; results have been generally disappointing, owing to the multi-faceted nature of tumour stroma.
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Isolated strategies to overcome specific immune targets have also met with limited success, likely owing to the presence of multiple immunoregulatory pathways within the pancreatic ductal adenocarcinoma microenvironment.
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In recognition of the functional complexity of the tumour microenvironment (TME), combining complementary stromal-targeted and immune-targeted treatment modalities to leverage the changes in the TME offers a more rational treatment approach.
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Points of biological convergence, such as stromal–immune crosstalk, including glutamine metabolism, focal adhesion kinase and transforming growth factor-β signalling, are promising targets for remodelling the TME into an antitumour milieu.
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Acknowledgements
W.J.H. is the recipient of an ASCO Young Investigator Award and an AACR Incyte Immuno-Oncology Research Fellowship, and is supported by NIH T32CA00971-38.
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W.J.H. could potentially receive patent-related royalties from Rodeo Therapeutics. E.M.J. receives commercial research grants from Aduro Biotech, Amgen, Bristol–Myers Squibb, Corvus and Hertix, has ownership interest in Aduro Biotech, and is a consultant and/or advisory board member for Achilles Therapeutics, Adaptive Biotechnologies, CStone Pharmaceuticals, Dragonfly Therapeutics, Genocea and the Parker Institute for Cancer Immunotherapy. She is a member of the National Cancer Advisory Board and the Chief Medical Advisor for the Lustgarten Foundation. L.Z. receives grant support from Amgen, Bristol–Myers Squibb, Halozyme, Inxmed, iTeos, Merck and NovaRock, and received royalties for licensing GVAX to Aduro Biotech. He is a paid consultant and/or advisory board member for Akrevia, Alphamab, Biosion, Datarevive, Foundation Medicine, Fusun Biopharmaceutical, Mingruzhiyao, NovaRock and Sound Biologics, and holds shares in Alphamab and Mingruzhiyao.
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Nature Reviews Clinical Oncology thanks I. Garrido-Laguna, A. Maitra, M. Moore and D. Ting for their contribution to the peer review of this work.
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Ho, W.J., Jaffee, E.M. & Zheng, L. The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities. Nat Rev Clin Oncol 17, 527–540 (2020). https://doi.org/10.1038/s41571-020-0363-5
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DOI: https://doi.org/10.1038/s41571-020-0363-5
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