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.<b>Significance:</b> 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.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/15/4253/F1.large.jpg <i>Cancer Res; 78(15); 4253-69. ©2018 AACR</i>.