Introduction: The successful eradication of tumor deposits by immunotherapy requires the generation of an appropriate primary and memory immune effector immune response as well as the establishment of a tumor micro-environment within that organ to target, traffic and amplify the appropriate immune response. B7-H1 is expressed on dendritic cells (DCs), macrophages, T/B cells and on various cancer cell lines. B7-H1 when bound to its T-cell receptor, programmed death-1 (PD-1) induces a negative regulatory signal inhibiting T cell responses. These are particularly attractive targets of therapy in metastatic colorectal cancer as the cancer and the liver microenvironment express B7H1, while tumor infiltrating CD8+ T cells express PD-1. It appears that cancer is able to exploit the B7H1-PD-1 inhibitory mechanism thus making the blockade of this interaction capable of enhancing our already validated vaccine platform of doubly attenuated Listeria Monocytogenes (LM).

Methods and Results: Isolated hepatic metastases were generated in Balb/c mice and treated with intraperitoneal injections of 0.1 x LD50 of LM on postoperative days 3, 6, 9. In addition, intravenous injection of a mouse anti-mouse B7-H1 blocking antibody was given on days 4,7,10 and compared to mice given vaccine alone, antibody alone, and no treatment. We analyzed immune cell populations in the liver with flow cytometry to define the activity, specificity and kinetics. After blockade of B7-H1 we performed survival analysis and in vitro studies for T cell proliferation of activated T cells.

Results: Mice treated with LM and B7-H1 showed a 60% survival, LM alone showed 30% survival, while antibody alone and untreated mice did not survive (Figure 1). We first demonstrated B7-H1 expression on colon cancer cell line CT26. We then found CD8+ T cells and conventional dendritic cells (cDC) treated with LM, showed an up-regulation of B7-H1. However, these receptors upregulation were both abgrogated when combined with B7H1 blocking antibody. When B7H1 blocking antibody was used alone, there was a decrease in B7H1 expression but an increased expression on PD-1 on CD8+ T cells. T cell proliferation assay in vitro showed sustained T cell activity with B7-H1 blockade even in the presence of tumor.

Conclusion Blockade of B7-H1 is an effective method of overcoming immune evasion and improves the efficacy of LM vaccine in the treatment of metastatic colorectal cancer to the liver.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2935.