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

Schmid, M. C., Quaranta, V., Rainer, C., Nielsen, S. R., Raymant, M. L., Ahmed, M. S., Engle, D. D., Taylor, A., Murray, T., Campbell, F., Palmer, D. H., Tuveson, D. A., Mielgo, A. (May 2018) Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. Cancer Res. ISSN 0008-5472

URL: https://www.ncbi.nlm.nih.gov/pubmed/29789416
DOI: 10.1158/0008-5472.can-17-3876

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 tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor 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. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor 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 tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.

Item Type: Paper
Subjects: diseases & disorders > cancer > metastasis
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date: 22 May 2018
Date Deposited: 25 May 2018 19:15
Last Modified: 25 May 2018 19:15
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36605

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