Abstract 4845: Reeducate the tumor microenvironment to improve the anticancer efficacy of adoptive T-cell therapy

Abstract

Abstract The hostile tumor microenvironment interferes with the function of efficient antitumor immune cells and constitutes a major obstacle for cancer immunotherapies. Here, we provide evidence that the immunosuppressive tumor microenvironment can be reeducated by an antiangiogenic agent to favor the development of adaptive antitumor immunity and to improve the efficacy of adoptive T cell therapy. Our results demonstrate that treatment with Brivanib, a novel small-molecule kinase inhibitor of VEGFRs and FGFRs, significantly enhanced the frequency and effector function of CD8+ cytotoxic T cells in tumor-bearing mice associated with significant reduction of tumor burden. Enhanced intratumoral infiltration of CD8+ T cells induced by Brivanib was associated with increased expression of chemokines (e.g., ccl3, ccl5, ccl11 and cxcl9) that regulates T cell trafficking and cell adhesion molecules (VCAM-1 and ICAM-1) on endothelial cells in the tumor microenvironment. Moreover, Brivanib treatment skewed the polarization of tumor-associated macrophages (TAM) away from the tumor-supporting M2 phenotype and restored the antigen presenting function of macrophages. Finally, Pretreatment of tumor-bearing animals with Brivanib prior to adoptive T cell transfer promotes in vivo proliferation, intratumoral infiltration and effector function of infused CD8+ T cells, resulting in better antitumor activity than either treatment alone. These findings indicate that Brivanib can be used to modulate the immunosuppressive microenvironment and as a potential adjuvant for enhancing the efficacy of cell-based cancer immunotherapy for cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4845. doi:1538-7445.AM2012-4845