Inhibition Of Cancer Stemness Sensitizes Colorectal Cancer To Immune Checkpoint Inhibitors

Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidences indicate that CSCs and CSC pathways, such as STAT3, beta-Catenin, CD44 and Nanog pathway, are involved in the immune evasion in cancers. With the exception of a small percentage of colorectal cancers (CRC) patients that display microsatellite instability (MSI), the vast majority of CRC patients have been found to be resistant to immune checkpoint therapies. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3, which lead to inhibition of multiple cancer stemness pathways, including Stat3 and β-catenin pathways. In this study, we investigate the effect of cancer stemness inhibition on sensitizing CRC to immune checkpoint inhibitors in preclinical models. In the syngeneic tumor model, anti-PD-1 antibody monotherapy produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD1 in the MSS CT26 CRC model. The anti-PD-1 antibody treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, including Nanog, CD44 and CD133, as well as enrichment of sphere-forming stemness-high cancer cells. BBI-608 was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. Combination of stemness inhibitor BBI-608 with anti-PD-1 antibody to treat CT26 tumors led to tumor complete response (CR) virtually in all treated CT26 tumors with 40% of the mice remain tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8 + T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by BBI-608 and anti-PD-1 antibody were able to reject CT26 tumors upon rechallenge, but not the unrelated breast cancer 4T1 tumors. Our data suggests cancer stemness pathways contribute to immunotherapy resistance in MSS CRC and inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition. This study provides compelling preclinical evidence to support the investigation of the combination of BBI608 with immune checkpoint inhibitors in CRC. Citation Format: Yuan Gao, Youzhi Li, Eric Hsu, Yuxin Wang, Janet Huang, Emily Brooks, Chiang J. Li. Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors [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 LB-140. doi:10.1158/1538-7445.AM2017-LB-140