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

Cancer Res. 2018 Aug 1;78(15):4253-4269. doi: 10.1158/0008-5472.CAN-17-3876. Epub 2018 May 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Granulins
  • Programmed Cell Death 1 Receptor