DNASE1L3-mediated PANoptosis enhances the efficacy of combination therapy for advanced hepatocellular carcinoma
Jingchun Wang1, Yu Chen2, Yanquan Xu3
1Department of Gastroenterology, Second Affiliated Hospital, Army Medical University; Chongqing 400037, China.
Abstract:
Rationale: The introduction of combination therapy utilizing tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) has significantly altered the management of affected patients. However, the absence of predictive biomarkers to identify those who would derive the greatest benefit from this combination therapy underscores the necessity for further enhancements in its efficacy. Methods: In this study, we performed a proteomic analysis on surgical specimens from patients who either responded to or did not respond to combination therapy with sorafenib and programmed death-1 (PD-1) monoclonal antibody (mAb). We employed in vitro experiments, including immunocytochemistry, co-immunoprecipitation, and transmission electron microscopy, to elucidate the mechanism of DNASE1L3-induced PANoptosis. Additionally, we assessed the function of DNASE1L3 in combination therapy using a mouse liver orthotopic tumor model and clinical samples. Results: Our findings indicated that the levels of deoxyribonuclease 1 like 3 (DNASE1L3) were significantly elevated in the cohort of patients who responded to treatment, correlating with the sorafenib-induced programmed cell death (PCD) of HCC cells. Further experimentation revealed that DNASE1L3 facilitated the generation of double-strand deoxyribonucleic acid (dsDNA) breaks and activated the absent in melanoma 2 (AIM2) pathway during sorafenib-induced HCC cell death, ultimately culminating in PANoptosis. Moreover, DNASE1L3-induced PANoptosis augmented the activation of anti-tumor immunity within the tumor microenvironment (TME), thereby enhancing the efficacy of the combination therapy involving sorafenib and PD-1 mAb. Conclusion: Our findings offer valuable insights into the mechanisms underlying DNASE1L3's role in sorafenib sensitivity and position DNASE1L3 as a promising predictive biomarker and target for improving outcomes in combination therapy for HCC.
Insights
Deoxyribonuclease 1 like 3 (DNASE1L3) is elevated in patients responding to combination therapy for advanced hepatocellular carcinoma (HCC). DNASE1L3 promotes PANoptosis, enhancing anti-tumor immunity and improving treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Combination therapy with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors has advanced hepatocellular carcinoma (HCC) treatment.
- Predictive biomarkers are needed to optimize combination therapy efficacy for HCC patients.
Purpose of the Study:
- To identify predictive biomarkers for combination therapy in advanced HCC.
- To elucidate the mechanism of DNASE1L3 in sorafenib-induced cell death and combination therapy efficacy.
Main Methods:
- Proteomic analysis of HCC surgical specimens from patients with varying treatment responses.
- In vitro experiments (immunocytochemistry, co-immunoprecipitation, electron microscopy) to study DNASE1L3-induced PANoptosis.
- In vivo studies using a mouse liver orthotopic tumor model and clinical samples to assess DNASE1L3 function.
Main Results:
- Elevated DNASE1L3 levels correlated with positive response to sorafenib and PD-1 mAb combination therapy in HCC patients.
- DNASE1L3 induced double-strand DNA breaks and activated the AIM2 pathway, leading to PANoptosis during sorafenib treatment.
- DNASE1L3-induced PANoptosis enhanced anti-tumor immunity in the tumor microenvironment, boosting combination therapy effectiveness.
Conclusions:
- DNASE1L3 is a key mediator of sorafenib sensitivity in HCC.
- DNASE1L3 shows promise as a predictive biomarker for combination therapy in HCC.
- Targeting DNASE1L3 may improve outcomes for advanced HCC patients receiving combination therapy.
