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

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. 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: http://cancerres.aacrjournals.org/content/canres/78/15/4253/F1.large.jpg Cancer Res; 78(15); 4253-69. ©2018 AACR.

• Authors: Valeria Quaranta, Carolyn Rainer, Sebastian R Nielsen, Meirion L Raymant, Muhammad S Ahmed, Dannielle D Engle, Arthur Taylor, Trish Murray, Fiona Campbell, Daniel H Palmer, David A Tuveson, Ainhoa Mielgo, Michael C Schmid
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 15 Pg. 4253-4269 (08 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29789416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Granulins
• Programmed Cell Death 1 Receptor

Topics

• Adenocarcinoma (metabolism, pathology)
• Animals
• CD8-Positive T-Lymphocytes (metabolism, pathology)
• Carcinoma, Pancreatic Ductal (metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (physiology)
• Female
• Granulins (metabolism)
• Macrophages (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Pancreatic Neoplasms (metabolism, pathology)
• Programmed Cell Death 1 Receptor (metabolism)
• Tumor Microenvironment (physiology)