Inhibition of Hif-1Α Enhances Anti-Tumor Effects of Dendritic Cell-Based Vaccination in a Mouse Model of Breast Cancer Publisher Pubmed



Kheshtchin N¹ ; Arab S² ; Ajami M³ ; Mirzaei R¹ ; Ashourpour M⁴ ; Mousavi N⁵ ; Khosravianfar N⁴ ; Jadidiniaragh F^{4, 5, 6} ; Namdar A¹ ; Noorbakhsh F¹ ; Hadjati J¹ Show Affiliations
Source: Cancer Immunology# Immunotherapy Published:2016

Abstract

Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine. © 2016, Springer-Verlag Berlin Heidelberg.