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

Autor:	Saung MT; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Muth S; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Ding D; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Thomas DL 2nd; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Blair AB; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Tsujikawa T; Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.; Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA., Coussens L; Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, USA.; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA., Jaffee EM; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Zheng L; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.; The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.; Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. lzheng6@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2018 Nov 13; Vol. 6 (1), pp. 118. Date of Electronic Publication: 2018 Nov 13.
DOI:	10.1186/s40425-018-0435-6
Abstrakt:	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.
Databáze:	MEDLINE
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