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

Quaranta, V.; Rainer, C.; Nielsen, S. R.; Raymant, M.; Ahmed, M. S.; Engle, D.; Taylor, A.; Murray, T.; Campbell, F.; Palmer, D.; Tuveson, D.; Mielgo, A.; Schmid, M.

doi:10.1101/234906

bioRxiv · 10.1101/234906

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

Quaranta, V.·Rainer, C.·Nielsen, S. R.·Raymant, M.·Ahmed, M. S.·Engle, D.·Taylor, A.·Murray, T.·Campbell, F.·Palmer, D.·Tuveson, D.·Mielgo, A.·Schmid, M.

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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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Quaranta, V., Rainer, C., Nielsen, S. R., Raymant, M., Ahmed, M. S., Engle, D., Taylor, A., Murray, T., Campbell, F., Palmer, D., Tuveson, D., Mielgo, A., Schmid, M.. 2017-12-15. Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. https://doi.org/10.1101/234906

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