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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

Valeria Quaranta, Carolyn Rainer, Sebastian R. Nielsen, Meirion Raymant, Muhammad Shamsher Ahmed, Dannielle D. Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel Palmer, David A. Tuveson, Ainhoa Mielgo, Michael C. Schmid
doi: https://doi.org/10.1101/234906
Valeria Quaranta
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Carolyn Rainer
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Sebastian R. Nielsen
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Meirion Raymant
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Muhammad Shamsher Ahmed
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Dannielle D. Engle
2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
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Arthur Taylor
3Department of Cellular and Molecular Physiology, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Trish Murray
3Department of Cellular and Molecular Physiology, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Fiona Campbell
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Daniel Palmer
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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David A. Tuveson
2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
4Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
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Ainhoa Mielgo
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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Michael C. Schmid
1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
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  • For correspondence: mschmid@liverpool.ac.uk
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Abstract

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.

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Posted December 15, 2017.
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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer
Valeria Quaranta, Carolyn Rainer, Sebastian R. Nielsen, Meirion Raymant, Muhammad Shamsher Ahmed, Dannielle D. Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel Palmer, David A. Tuveson, Ainhoa Mielgo, Michael C. Schmid
bioRxiv 234906; doi: https://doi.org/10.1101/234906
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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer
Valeria Quaranta, Carolyn Rainer, Sebastian R. Nielsen, Meirion Raymant, Muhammad Shamsher Ahmed, Dannielle D. Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel Palmer, David A. Tuveson, Ainhoa Mielgo, Michael C. Schmid
bioRxiv 234906; doi: https://doi.org/10.1101/234906

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