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

Quaranta, Valeria, Rainer, Carolyn, Nielsen, Sebastian, Raymant, Meirion, Ahmed, Muhammad ORCID: 0000-0001-6163-8102, Engle, Dannielle, Taylor, Arthur ORCID: 0000-0003-2028-6694, Murray, Trish, Campbell, Fiona, Palmer, Daniel ORCID: 0000-0002-7147-5703
et al (show 3 more authors) (2018) Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. Cancer Research, 78 (15). pp. 4253-4269.

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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. Although metastatic PDAC tumors are largely resistant to anti–PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the antitumor 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. Significance: These findings uncover a mechanism by which metastatic PDAC tumors evade the immune response and provide the rationale for targeting granulin in combination with immune checkpoint inhibitors for the treatment of metastatic PDAC. Graphical Abstract:

Item Type: Article
Uncontrolled Keywords: CD8-Positive T-Lymphocytes, Cell Line, Tumor, Macrophages, Animals, Mice, Inbred C57BL, Mice, Adenocarcinoma, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Drug Resistance, Neoplasm, Female, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Granulins
Depositing User: Symplectic Admin
Date Deposited: 21 May 2018 07:18
Last Modified: 19 Jan 2023 06:33
DOI: 10.1158/0008-5472.CAN-17-3876
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