Abstract B21: CD1 d-expressing breast cancer cells promote iNKT-mediated antitumor immunity in a mouse model of breast cancer bone metastasis

Overcoming tumor tolerance and immune suppression remains a formidable obstacle to the development of immunotherapeutics that harness the immune system to eradicate breast cancer. We have developed a syngeneic mouse model to study mechanisms of tumor tolerance and immune suppression during breast cancer bone metastasis. Comparative analysis of low metastatic vs. highly bone metastatic tumor cells isolated from mice revealed several important genetic alterations related to immune control of tumor progression. Of these, a significant downregulation of cd1d1 was observed in the highly bone metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells that bridge the innate and adaptive immune response to cancer, known as invariant natural killer T (iNKT) cells. Activated iNKT cells mediate antitumor immunity in cell culture and in mouse models in vivo. Clinically, iNKT levels are significantly reduced in solid tumors, and this reduction is correlated with a poor prognosis in many types of cancers, including breast cancer. It is well known that the majority of advanced breast cancer patients present with bone metastases, and NKT cells have been shown to comprise a significant portion of the T cells found in healthy bone marrow. We hypothesize that downregulation of CD1d by breast cancer cells enables evasion of iNKT immune surveillance and inhibition of iNKT-mediated antitumor immunity, and may be an important prerequisite for the ability of breast cancer cells to colonize bone. In this study, we demonstrate in a mouse model of breast cancer bone metastasis that tumor cells expressing CD1d can induce direct iNKT-mediated cytolysis in a CD1d-dependent manner in vitro, and demonstrate increased CD1d-dependent iNKT-mediated antitumor immunity in vivo. Using transgenic knockout (KO) models, we show that the ability of CD1d-expressing tumor cells to metastasize to bone is dependent on the presence of CD1 d-restricted NKT cells. The results of this study further support research into therapeutic strategies that boost iNKT-mediated antitumor immunity for the treatment of advanced metastatic breast cancer. In addition, we propose the use of our novel mouse model of breast cancer bone metastasis as an ideal system for conducting further studies into mechanisms of immune regulation of breast cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B21.