Abstract 3808: MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs

Abstract

Abstract Kupffer cells (KCs) account for 15% of the total liver cells. However, their roles in hepatocellular carcinoma (HCC) is poorly described. Clec4fCre-tdTomato knock-in mice expressing Cre recombinase and tdTomato-NLS under the KC-specific Clec4f promoter were hydrodynamically injected with oncogenic AKT and Nras (AKT/Ras) to induce HCC. A LoxP-stop-LoxP (LSL) system was used to express miR-206 in KCs of mice. AKT activation was observed in hepatocytes and KCs of HCC patients. Hydrodynamic injection (HDI) of AKT/Ras led to activation of AKT signaling in KCs and hepatocytes. AKT/Ras mice developed lethal HCC within 6-8 weeks post injection. Activation of AKT signaling led to M2 polarization of KCs, increased hepatic Tregs and exhaustion of CTLs. MicroRNA (miR) profiling revealed that AKT/Ras impaired miR-206 biogenesis in KCs by driving translation of Yin Yang 1 (YY1), a transcription repressor of miR-206. HDI of miR-206 into AKT/Ras mice fully prevented HCC, while all control mice died of HCC 6-8 weeks post injection. However, HDI of miR-206 only transfected ~ 20% of hepatocytes, indicating that it is unreasonable to conclude that the full prevention of HCC in AKT/Ras/miR-206 mice is caused by inhibited proliferation of HCC cells. We, therefore, posited that miR-206-mediated recovery of immune surveillance, at least in part, accounted for the full prevention of HCC in AKT/Ras/miR-206 mice. We next used the LSL system to overexpress miR-206 in KCs of Clec4fCretdTomato mice injected with AKT/Ras. KC-specific expression of miR-206 fully prevented HCC in AKT/Ras mice, while 100% control mice died of HCC. Mechanistically, AKT signaling in KCs drove CCL22 (C-C motif chemokine ligand 22) production by phosphorylating β-catenin that activates transcription of Ccl22. In contrast, miR-206 disrupted β-catenin signaling by targeting LEF1 (lymphoid enhancer-binding factor 1), an “architectural” transcription factor of β-catenin. CCL22 recruits Tregs. Indeed, KC-specific expression of miR-206 led to elevated CCL22, M2 to M1 transition of KCs, reduced hepatic Tregs, and elevated CTLs. Depletion of CTLs in AKT/Ras mice fully offset the ability of miR-206 to prevent HCC. Conclusions: AKT-educated KCs initiate Treg recruitment via a regulatory loop consisting of YY1, β-catenin/LEF1, miR-206, and CCL22; once this loop is activated, AKT activates β-catenin axis, which drives CCL22 production, Treg recruitment and HCC growth; while KC-specific expression of miR-206 reversed this process by blocking β-catenin axis in KCs. miR-206 represents a novel immunotherapy against HCC. Citation Format: Guisheng Song, Ningning Liu. MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3808.