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, 78 (15). pp. 4253-4269. ISSN 0008-5472
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 CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 22 May 2018 |
| Date Deposited: | 25 May 2018 19:15 |
| Last Modified: | 15 Nov 2023 18:25 |
| PMCID: | PMC6076440 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36605 |
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