Breast cancer is the most common cancer in Canadian women and the second leading cause of cancer deaths. Given that most mammary tumors are surgically resectable and over 90% of breast cancer-associated deaths are due to metastasis, new therapeutic strategies targeting metastasis are required. Natural killer T (NKT) cells are a rare population of immune cells that have been shown to limit primary tumor growth and target distant metastatic disease in various animal models. We have shown that NKT cell activation improves survival in a model of post-surgical metastatic breast cancer. We are now expanding this work to determine whether NKT cell activation can be combined with chemotherapies to improve outcomes. In our model, 4T1 mammary carcinoma cells were injected into the mammary fatpad of syngeneic BALB/c mice. Tumors were resected at day 12, and mice were treated with cyclophosphamide or gemcitabine. On day 17, NKT cells were activated by transfer of dendritic cells loaded with the glycolipid antigen α-GalCer. We also examined whether Gemcitabine or mafosphamide (active component of cyclophosphamide) would induce immunogenic cell death of 4T1 cells in culture. Chemotherapeutics did not affect NKT cell activation as measured by serum IFNγ levels. Treatment with cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cells alone reduced metastasis and prolonged survival. Combined treatments significantly enhanced survival. NKT cell activation decreased the frequency and immunosuppressive function of myeloid derived suppressor cells (MDSCs). Treatments resulted in enhanced tumor specific immunity as surviving mice exhibited slower tumor growth following secondary tumor challenge. Gemcitabine and mafosphamide also increase the immunogenicity of cancer cells in vitro by increasing the exposure/release of MHCI, MHCII, CD1d, Calreticulin, HMGB1 and ATP. NKT cell activation therapy can successfully be combined with low doses of Gemcitabine or cyclophosphamide to enhance protection against tumor metastasis and recurrence. This work provides a clear rationale for combining chemotherapy with NKT cell immunotherapy to target metastatic disease in the clinical setting.
Citation Format: Simon Gebremeskel, Kaitlyn Tanner, Lynnea Lobert, Brent Johnston. Combining natural killer T cell immunotherapy with chemotherapy induced immunogenic cell death to target post-surgical breast cancer metastasis [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B047.
- ©2016 American Association for Cancer Research.