Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 15; pp. 4253 - 4269
• Main Authors: Quaranta, Valeria, Rainer, Carolyn, Nielsen, Sebastian R, Raymant, Meirion L, Ahmed, Muhammad S, Engle, Dannielle D, Taylor, Arthur, Murray, Trish, Campbell, Fiona, Palmer, Daniel H, Tuveson, David A, Mielgo, Ainhoa, Schmid, Michael C
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.08.2018
• Subjects: Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Colony-stimulating factor; Cytotoxicity; Drug Resistance, Neoplasm - physiology; Female; Granulin; Granulins - metabolism; Immune checkpoint inhibitors; Immune response; Immune system; Inhibition; Inhibitors; Lymphocytes; Lymphocytes T; Macrophage colony-stimulating factor; Macrophages; Macrophages - metabolism; Macrophages - pathology; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PD-1 protein; Programmed Cell Death 1 Receptor - metabolism; Stroma; Tumor Microenvironment - physiology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-3876

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. 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. http://cancerres.aacrjournals.org/content/canres/78/15/4253/F1.large.jpg .