Abstract 962P
Background
Stereotactic radiotherapy (SBRT) has shown promising for unresectable hepatocellular carcinoma (HCC) due to its ability to modulate the tumor immune microenvironment. Methyl-CpG binding domain protein 3 (MBD3) is highly expressed in HCC and negatively correlated with prognosis. However, the role of MBD3 in the radioimmunology of SBRT in HCC remains unclear.
Methods
The expression and correlation of MBD3 and programmed cell death ligand 1 (PD-L1) were analyzed in HCC tissues before and after SBRT by immunohistochemistry (IHC). The mechanic regulations of MBD3 in the radioimmunology of SBRT in HCC were investigated both in vitro and in vivo studies.
Results
We observed a significant increase of PD-L1 in HCC after SBRT, which was associated with decreased MBD3 expression. As the radiation dose increased, MBD3 gradually degraded, while PD-L1 gradually upregulated in human and murine liver cancer cells. Through RNA sequencing, KEGG enrichment analysis and in vitro experiments, we identified that IL-6 was massively activated and released, leading to the activation of the JAK1/STAT3 signaling pathway, and ultimately resulted in the upregulation of PD-L1, which were induced by MBD3 degradation in liver cancer cells by irradiation. In vivo experiments showed that the combination of SBRT and PD-L1 blockade significantly enhanced the antitumor efficacy in the murine orthotopic model of HCC, partly dependent on the increased infiltration of IFNγ+CD8+T cells in the tumor. We also found that SBRT reactivated proteinase-activated receptor 2 (PAR2) to promote the release of IL-6, activating the JAK1/STAT3 signaling pathway, leading to the upregulation of PD-L1 through relieving the inhibition of F2RL1 (encoding PAR2) mediated by the deacetylation of the MBD3/NuRD complex. Our findings were further confirmed by IHC analysis of the above proteins in HCC tissues before and after SBRT.
Conclusions
Our study suggests that SBRT can reprogram the tumor immune microenvironment by activating the PAR2/IL-6/JAK1/STAT3 axis through MBD3 degradation, leading to PD-L1 upregulation, which may help develop new therapeutic strategies targeting PD-L1 to improve the efficacy of SBRT in HCC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1009P - Network meta-analysis of first-line systemic therapies for advanced hepatocellular carcinoma: A comparison of objective response rates
Presenter: Gagandeep Kaur
Session: Poster session 18
1010P - A parametric network meta-analysis of first-line systemic therapies for advanced hepatocellular carcinoma related to overall survival
Presenter: Akanksha Sharma
Session: Poster session 18
1011P - A prospective study of TACE combined with lenvatinib plus sintilimab for HCC with portal vein tumor thrombus
Presenter: Xiaoyan Ding
Session: Poster session 18
1012P - First-in-human study of ABSK-011, a novel, highly selective fibroblast growth factor receptor (FGFR) 4 inhibitor for treating advanced hepatocellular carcinoma (HCC) with FGF19 overexpression
Presenter: Ann-Lii Cheng
Session: Poster session 18
1013TiP - Refinement and validation of a comprehensive clinical diagnostic model (GAMAD) for early detection of hepatocellular carcinoma: A multicenter, prospective study protocol
Presenter: Tian Yang
Session: Poster session 18
1014TiP - Efficacy and safety of recombinant human adenovirus type 5 injection combined with transhepatic arterial embolization sequential thermal ablation for medium-and high-risk recurrent liver cancer: a prospective, open-label, randomized controlled study
Presenter: Jianjun Li
Session: Poster session 18
1015TiP - A Prospective, phase II clinical study of tislelizumab monotherapy or in combination with lenvatinib for neoadjuvant treatment of resectable hepatocellular carcinoma
Presenter: Tianqiang Song
Session: Poster session 18