Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo
Melek M E Sunay1, Jeremy B Foote2, James M Leatherman3
1Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD 21287, USA; Johns Hopkins University School of Medicine, Graduate Program in Pathobiology, Baltimore, MD 21287, USA.
Abstract:
The tumor microenvironment (TME) is established and maintained through complex interactions between tumor cells and host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in both tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM). In vitro, sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Sorafenib also interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, as well as cyclin D expression, but did not affect HER-2 or AKT signaling. In vivo, single agent sorafenib disrupted the tumor-associated vasculature and induced tumor cell apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that both CD4+ and CD8+ T cells were required for tumor regression. Sorafenib treatment did not impact the rate of tumor clearance induced by vaccination with 3T3neuGM in tumor-bearing FVB/N mice relative to either sorafenib treatment or vaccination alone. In vivo studies further demonstrated that sorafenib enhanced the accumulation of both CD4+ and CD8+ T cells into the TME of vaccinated mice. Together, these findings suggest that GM-CSF-secreting cellular immunotherapy may be integrated with sorafenib without impairing vaccine-based immune responses.
Insights
Sorafenib, a multi-kinase inhibitor, effectively regresses HER-2 breast tumors by disrupting vasculature and inducing apoptosis, requiring CD4+ and CD8+ T cells. It enhances T cell infiltration when combined with a GM-CSF secreting vaccine.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- The tumor microenvironment (TME) involves complex interactions between tumor and stromal cells, suggesting multi-targeted therapies are effective.
- Sorafenib, a multi-kinase inhibitor, impacts tumor cells and stromal cells.
- HER-2 (neu) overexpression is a target in breast cancer therapy.
Purpose of the Study:
- To explore the immune-modulating effects of sorafenib in a HER-2 overexpressing breast tumor model.
- To evaluate sorafenib alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM).
Main Methods:
- In vitro studies assessed sorafenib's effect on NT2.5 tumor cell growth, apoptosis, and signaling pathways (ERK MAPK, p38 MAPK, STAT3, HER-2, AKT).
- In vivo studies utilized a murine HER-2 (neu) overexpressing breast tumor model (NT2.5) in FVB/N mice.
- Immune depletion studies and combination therapy with 3T3neuGM vaccine were performed.
Main Results:
- Sorafenib inhibited NT2.5 cell growth and induced apoptosis in vitro, interfering with specific signaling pathways but not HER-2 or AKT.
- In vivo, sorafenib alone caused tumor regression by disrupting vasculature and inducing apoptosis, dependent on CD4+ and CD8+ T cells.
- Combination therapy did not impair vaccine efficacy and enhanced CD4+ and CD8+ T cell infiltration into the TME.
Conclusions:
- Sorafenib demonstrates anti-tumor activity and immune-modulating effects in a HER-2 breast cancer model.
- Sorafenib enhances T cell responses within the tumor microenvironment.
- GM-CSF secreting cellular immunotherapy can be integrated with sorafenib without compromising vaccine-based immune responses.
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