Enhancing HER2/neu Specific T-cell Therapy by Targeting the Tumor Endothelium (41.11)

Abstract

Abstract Success of adoptive T cell therapy for cancer can be hindered by the tumor stroma, which consists of factors that not only promote tumor growth but also prevent egress of tumor-specific T cells into the tumor parenchyma. We recently demonstrated that T cell transit through tumor vasculature is regulated by the endothelin B receptor (ETBR). In addition, the endothelin axis plays a major role in tumor cell growth, apoptosis, angiogenesis and metastasis. The purpose of this study was to determine if, in breast cancer, targeting endothelin-1 via ETBR blockade might abrogate the endothelial barrier and increase T cell homing to tumors, thereby augmenting the efficacy of HER2/neu antigen specific Type 1 helper (Th1) cell therapy of spontaneous HER2/neu+ mammary tumors. By reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), we found overexpression of ETBR in peritumoral stroma of spontaneous mammary tumors derived from HER2/neu transgenic mice. We treated tumor-bearing mice with HER2/neu specific T cells alone or HER2/neu specific T cells + BQ-788, a specific ETBR inhibitor peptide. The addition decreased tumor growth by 84%. Thus, in this model of HER2/neu mediated breast cancer, targeting the tumor endothelium can significantly enhance the clinical efficacy of HER2/neu specific Th1 cells. Studies are underway to evaluate the biological mechanisms induced by endothelin targeting that cooperate with T cell therapy in the resulting significant success of the combined treatment. The data provide a rationale for combining tumor antigen specific T cell therapy with endothelin blockade to induce an effective anti tumor response in breast cancer.