Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. Issue 1 (13th November 2018)

• Record Type: Journal Article
• Authors: Saung, May Tun; Muth, Stephen; Ding, Ding; Thomas, Dwayne L.; Blair, Alex B.; Tsujikawa, Takahiro; Coussens, Lisa; Jaffee, Elizabeth M.; Zheng, Lei
• Is Part Of: Journal for immunotherapy of cancer. Volume 6:Issue 1(2018)
• Publication Date: 2018-11-13
• Subjects: Pancreatic ductal adenocarcinoma -- Lymphoid aggregates -- Cytotoxic T-cells -- Tumor associated macrophages -- Dendritic cells -- PD-1 -- CSF-1R -- CD137 -- GVAX -- Interferon-γ; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-018-0435-6
• Languages: English
• ISSNs: 2051-1426

Abstract

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.