Abstract
Abstract Surface over-expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) has recently been identified as a mechanism used by metastatic breast cancer cells to provide pro-survival advantages. It has been previously shown that the metastatic and immune-resistant mouse cervical cancer cell line, A17 has a significantly increased expression of VCAM-1 compared with the primary parental tumor cell line, TC1-P0. Using this metastatic tumor model, we first modulated the surface expression levels of VCAM-1 on A17 in vitro by using an shRNA knockdown approach. We then inoculated these cells intra-venously (iv) and subcutaneously (sq) into C57BL/6 background mice and athymic nude mice to interrogate how VCAM-1 expression affects surrounding immune cell interactions within the tumor microenvironment. To further characterize VCAM-1 dependent immune responses, we used intravital 2-photon laser-scanning microscopy (2P-LPS) to dynamically visualize immune-tumor cells interaction. We observed that VCAM-1 down-regulation reduces the primary tumor growth kinetics in C57BL/6 mice but exhibited similar growth kinetics in nude mice, suggesting that VCAM-1 levels are not responsible for the intrinsic primary tumor growth differences in vivo. Moreover, VCAM-1 down-regulated cell lines showed decreased lung metastasis in both immune-competent mice and athymic nude mice. Furthermore, the metastatic lung parenchyma in mice injected with the non-silencing shVCAM-1 control exhibited immune cell infiltrates with a predominance of M2 polarized macrophages and an altered cytokine production. This may be responsible for decreased susceptibility to immune surveillance. Together, our results demonstrate that tumor-associated VCAM-1 expression helps aggressive tumors circumvent effective immune surveillance, and may represent a target for the development of immune-mediated therapy in metastatic cervical cancer. Citation Format: Francesca Scrimieri, Iuliana Dit Bobanga, Saada Eid, David J. Corn, Deborah Barkauskas, Jay Jay Myers, Alex Y. Huang. VCAM-1 enhances immune evasion in a murine model of metastatic cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2014-1174
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