Type I T cells sensitize treatment refractory tumors to chemotherapy through inhibition of oncogenic signaling pathways.

backgroundThe most common clinical outcome observed after treatment with immune checkpoint inhibitor antibodies is disease stabilization. Using vaccines to generate high levels of tumor antigen-specific T-helper 1 (Th1), we show that tumors not eradicated by vaccination demonstrate prolonged disease stabilization. We evaluated the mechanism by which type I T cells inhibit disease progression and potentially influence the subsequent clinical response to standard therapy in treatment refractory cancers.

methodsWe employed a meta-analysis of studies with tumor growth from four different vaccines in two different mammary cancer models. The T-cell subtype and cytokine essential for vaccine-induced tumor inhibition was determined by in vivo neutralization studies and immunohistochemistry. The role of interferon gamma (IFN-γ) in receptor tyrosine kinase and downstream signaling was determined by immunoblotting. The role of suppressor of cytokine signaling 1 (SOCS1) on IFN-γ signaling was evaluated on SOCS1-silenced cells with immunoblotting and immunoprecipitation. The effect of vaccination on growth factor receptor signaling pathways, performed in both luminal (TgMMTVneu) and basal (C3(1)-Tag) mammary cancer models treated with paclitaxel or an anti-HER2-neu monoclonal antibody were assessed via immunoblotting.

resultsImmunization with an epitope-based vaccine targeting a representative tumor antigen resulted in elevated tumor trafficking Tbet+CD4 T cells, decreased tumor proliferation and increased apoptosis compared with control vaccinated mice. The resulting disease stabilization was dependent on IFN-γ-secreting CD4

conclusionsThese data suggest the clinical activity of type I T cells extends beyond direct tumor killing and immune therapies designed to increase type I T cells and could be integrated into standard chemotherapy regimens to enhance therapeutic efficacy.