Dual Inhibition Of Cancer Sternness And Immune Checkpoint Genes By Targeting Stat3

Highly malignant stemness-high cancer cells, also termed cancer stem cells, have been found to hijack stemness genes important for embryonic stem cells to acquire a state of high-stemness. Cancer stemness has been associated with enhanced tumorigenicity and resistance to chemotherapies. Moreover, stemness-high cancer cells have been isolated from a variety of human cancer types. Therefore, targeting cancer stemness holds significant promise for advancing cancer treatment. Recent clinical success with antibodies targeting PD1 and PDL1 has validated that cancer cells can hijack immune checkpoint genes to subvert endogenous anticancer surveillance by the immune system. It is, therefore, highly desirable to develop therapeutics that simultaneously target both cancer cell stemness and immune checkpoints. The transcription factor Signal Transducer and Activator of Transcription 3 (Stat3) is activated by a multitude of upstream oncogenic pathways and cytokine receptors. Aberrant and constitutive activation of Stat3 has been found in a wide variety of human cancers, and has also been implicated in cancer cell proliferation, survival, and immune evasion. By using aiRNA (asymmetric RNA duplexes) we have achieved potent Stat3 silencing with precision in stemness-high cancer cells. We observed that Stat3 silencing leads to simultaneous down regulation of cancer cell stemness and immune checkpoint gene expression. Treatment of stemness-high cancer cells with BB608, a small molecule inhibitor of Stat3, led to simultaneous inhibition of stemness-high cancer cell survival and self-renewal, as well as downregulation of immune checkpoint genes, including IDO1 in vitro and in vivo. Furthermore, while expression of stemness genes and immune checkpoint genes in tumor tissues are known to predict poor patient survival, patients with higher expression levels of stemness genes and immune checkpoint genes showed prolonged overall survival after treatment with BB608 in clinical trials. Targeting Stat3 is, therefore, a promising strategy to achieve dual inhibition of cancer cell stemness and immune evasion. Citation Format: Yuan Gao, Sarah Keates, Eric Hsu, Janet Huang, Emily Brooks, Matt Hitron, Youzhi Li, Harry A. Rogoff, Chiang Li. Dual inhibition of cancer stemness and immune checkpoint genes by targeting Stat3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2222.