Abstract 2005: Synergistic effect of phenyl alpha-galactosylceramide C34 and chemotherapy on 4T1-tumor bearing mouse model

Abstract

Abstract Invariant natural killer T (iNKT) cells represent a unique subpopulation of innate immune cells which have immune modulatory effects on many immune effector cells such as CD4 T cells and CD8 T cells. Alpha-galactosylceramide (a-GalCer) is a well-known iNKT-stimulating glycolipid. Using a-GalCer as a template, we have generated a more potent a-GalCer analog C34, which contains two aromatic rings at the acyl chain and demonstrated its anti-cancer effect on tumor bearing mice model. It has been reported that NKT cells killed cancer cell lines treated with chemotherapy agents through TRAIL- and FasL-mediated pathways. In this study, we evaluated the anti-cancer effects of chemotherapy and C34 on tumor-bearing mouse model. First, BALB/c mice bearing 4T1 breast cancer were injected with various dose of chemotherapy agents weekly x 5 and the sub-optimal dose of docetaxel and doxorubicin was determined to be 0.5 mg/Kg. Similarly, sub-optimal dose of cisplatin and docetaxel in TC1 lung cancer-bearing C57BL/6 mice was determined to be 1 mg/Kg and 2 mg/Kg, respectively. In both tumor models, the suboptimal dose of C34 was found to be 0.1 ug per mouse. The treatment schedules of combination of chemotherapy and C34 were examined by administration of C34 at the same day (0D), three days (-3D) and one day (-1D) before chemotherapy and one day (+1D) after chemotherapy. We observed a survival benefit in mice injected with C34 one day after docetaxel treatment in 4T1-bearing mice as compared to those treated with the other schedules. Moreover, the survival of mice was significantly prolonged when C34 was injected three days after cisplatin treatment in TC1-bearing mice (median survival: 46 days for cisplatin and 55 days for cisplatin+C34, log-rank test p = 0.041). In the 4T1 tumor microenvironment, we found the number of CD3+CD8+ T cells was significantly greater in mice treated with docetaxel+C34 (23,536 +/- 901.4) than those treated with docetaxel only (2,270 +/- 1,536, t-test P < 0.0001). In addition, the number of PD1+ CD8 T cells was slightly higher, but did not reach statistical significance (t-test p = 0.3), in mice treated with docetaxel+C34 (23.3 +/- 8.5) than in mice treated with docetaxel only (14.6 +/- 10.1). In short, we have established an optimal treatment schedule for the combination of C34 and chemotherapy that showed synergistic anti-tumor efficacy. We also demonstrated that C34 could increase the number of CD8+ T cells in the tumor microenvironment in mice receiving chemotherapy. These results indicate that combination of C34 and chemotherapy administered with an optimal treatment schedule might have synergistic therapeutic efficacy for patients with lung cancer and breast cancer. Citation Format: Jung-Tung Hung, Jen-Chien Wu, Tsai-Hsien Hung, Jing-Rong Huang, John Yu, Alice L. Yu. Synergistic effect of phenyl alpha-galactosylceramide C34 and chemotherapy on 4T1-tumor bearing mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2005. doi:10.1158/1538-7445.AM2017-2005