Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer

May Tun Saung, Stephen Muth, Ding Ding, Dwayne L. Thomas, Alex B. Blair, Takahiro Tsujikawa, Lisa Coussens, Elizabeth M. Jaffee, Lei Zheng

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/αPD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/αPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS: Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS: High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p < 0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p < 0.05), but not mature dendritic cells (p = 0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/αPD-1 ("pre/post-αCSF-1R + αPD-1 + GVAX") enhanced the survival rate compared to GVAX/αPD-1 dual therapy (p = 0.005), but administering anti-CSF-1R only before GVAX/αPD-1 did not (p = 0.41). The "pre/post-αCSF-1R + αPD-1 + GVAX" group also had higher intra-tumoral infiltration of PD-1 + CD8+ and PD-1 + CD4+ T-cells compared to αPD-1/GVAX (p < 0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1 + CD137 + CD8+, PD-1 + CD137 + CD4+ and PD-1 + OX40 + CD4+ T-cells (p < 0.001). These PD-1 + CD137 + CD8+ T-cells expressed high levels of interferon-γ (median 80-90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001). CONCLUSIONS: The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC.

Original languageEnglish (US)
Number of pages1
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - Nov 13 2018

Keywords

  • CD137
  • CSF-1R
  • Cytotoxic T-cells
  • Dendritic cells
  • GVAX
  • Interferon-γ
  • Lymphoid aggregates
  • Pancreatic ductal adenocarcinoma
  • PD-1
  • Tumor associated macrophages

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint Dive into the research topics of 'Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer'. Together they form a unique fingerprint.

  • Cite this