Project Details
Description
Abstract
Hepatocellular carcinoma (HCC) ranks the third in cancer-related mortality because of ineffective therapy.
Intratumoral accumulation of regulatory T-cells (Tregs), which suppresses antitumor immunity, has been identified
in HCC. Despite the extensive research of microRNAs in HCC, their roles in regulating immunosuppression are
poorly described. Aberrant activation of AKT (v-akt murine thymoma viral oncogene homolog 1) and Nras
(neuroblastoma ras viral oncogene homolog) (Ras) was observed in Kupffer cells (KCs) and hepatocytes (HCs)
in 74% of HCC patients. Hydrodynamic injection (HDI) of activated forms of AKT and Nras (AKT/Ras) into mice
triggered the development of lethal HCC within 6-8 weeks. MiRNA profiling revealed that miR-15a and miR-16-
1 cluster (miR-15a/16) was reduced in KCs from HCC tumors of AKT/Ras mice and patients. KC-specific
expression of miR-15a/16 fully prevented growth of aggressive HCC in AKT/Ras mice, while 100% of AKT/Ras
mice died from lethal tumor burden within 6-8 weeks post-injection. KC-specific expression of miR-15a/16 also
led to a significant regression of HCC tumors in AKT/Ras mice bearing tumors. Mechanistically, AKT/Ras
reprogrammed the transcriptome of KCs toward M2 polarization of KCs and drove a significant increase in serum
C-C motif chemokine 22 (CCL22) and mRNA levels of Ccl22 in KCs of AKT/Ras mice. In contrast, miR-15a/16
reversed this process and inhibited CCL22 overproduction by directly targeting NF-κB that activates transcription
of Ccl22. CCL22 recruits Tregs via CCR4 (C-C chemokine receptor type 4). Indeed, additional treatment of CCL22
recovered immunosuppression and growth of HCC that was fully prevented by miR-15a/16 in AKT/Ras mice.
We hypothesize that AKT/Ras-educated KCs initiate hepatic recruitment of Tregs by overproducing CCL22,
thereby promoting HCC development; while KC-specific expression of miR-15a/16 suppresses hepatic recruitment
of Tregs and HCC development by attenuating CCL22 production. The objective of this project is to elucidate the
role of AKT/Ras-educated KCs in promoting immune suppression that promotes growth of HCC, while miR-15a/16
reverses this process by inhibiting NF-κB signaling in KCs. The long-time goal is to develop KCs as a therapeutic
target and miR-15a/16 as a novel immunotherapy against HCC. Three specific aims are designed to test our
hypothesis. Specifically, we will (1) unravel the mechanism(s) by which AKT/Ras-educated KCs promote
immunosuppression and HCC development. (2) establish the mechanism(s) by which miR-15a/16 drives
antitumor immunity; and (3) evaluate the therapeutic potential of miR-15a/16 against HCC with divergent
backgrounds. The combination of strong preliminary data and a logical and rationally based experimental design
make this project highly feasible. We expect that this study will provide a novel insight into the immunosuppression
mechanisms in HCC and facilitate the design of KCs as a novel therapeutic target and miR-15a/16 as a rational
immunotherapy against HCC.
Status | Active |
---|---|
Effective start/end date | 8/22/22 → 7/31/24 |
Funding
- National Cancer Institute: $359,312.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.