Clin Mol Hepatol > Volume 30(4); 2024 > Article
Lim and Cho: Correspondence to editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”
Dear Editor,
We extend our appreciation to Ahn and Yang for their valuable insights [1] provided on our study [2]. Their commentary offers a thorough evaluation of the effectiveness of multiomics methodologies in discovering new blood-based biomarkers specific to the etiology of hepatocellular carcinoma (HCC). Divergent transcriptomic and immune profiles distinguish hepatitis B virus (HBV)-associated HCC (HBV-HCC), marked by upregulation of immune response-related genes, from nonviral HCC (NV-HCC), characterized by heightened expression of metabolic genes [2]. These distinctions underscore the importance of delineating etiology-specific mechanisms in HCC to advance tailored diagnostic and therapeutic interventions.
Ahn and Yang note that in cases of HBV-HCC, where biomarkers are associated with immune response pathways, patients could potentially benefit from emerging immunotherapies or targeted treatments aimed at altering the immune milieu [1]. Notably, findings from phase II and III trials (KEYNOTE-224 [3] and KEYNOTE-394 [4]) consistently demonstrate favorable responses to pembrolizumab, a PD1-targeting monoclonal antibody, among a significant proportion of HBV+ HCC patients. The enhanced sensitivity of HBV+ HCC to immune checkpoint inhibitors may be attributed to elevated expression levels of immune checkpoint genes, such as PD-1, CTLA-4, TIGIT, and HAVCR2, as well as the presence of more abundant regulatory T cells (Tregs), exhausted CD8+ T cells, and M1-like macrophages expressing MMP9, thus contributing to a more immunosuppressive and exhausted tumor microenvironment in HBV+ HCC compared to NV-HCC [5]. Furthermore, in a mouse model of chronic HBV infection, it has been demonstrated that HBV infection leads to simultaneous increases in PD-L1 levels on liver-resident NK cells and PD-1 expression on intrahepatic T cells [6]. These findings highlight the impact of HBV on shaping tumor immunity, laying the groundwork for the development of improved immunotherapeutic approaches for HCC originating from various causes.
As Ahn and Yang pointed out, the non-invasive and scalable nature of liquid biopsy, which offers clinically relevant insights into tumor biology [7], could facilitate the incorporation of the identified biomarkers into routine blood tests, particularly in areas with high HBV prevalence [1]. In our investigation, SH3PXD2B and CD70 exhibited notable diagnostic efficacy in distinguishing early-stage HBV-HCC and NV-HCC, respectively, from at-risk patients with metabolic dysfunction-associated steatohepatitis (MASH) or cirrhosis. To facilitate their clinical utility, it is crucial to assess their discriminatory capacity for early detection of HCC through randomized clinical trials conducted on larger and more diverse patient cohorts. Moreover, the establishment of a ‘universal’ cutoff defining high expression levels and stratifying patients warrants attention. While the universal cutoff, established at the intersection of sensitivity and specificity, serves as a standard metric, its applicability in clinical practice may not always align with optimal diagnostic outcomes [8]. In the pursuit of enhancing diagnostic efficacy, the emphasis leans toward elevating sensitivity, even if this entails a trade-off with specificity, thereby increasing the likelihood of false-positive results. The rationale behind prioritizing sensitivity stems from the profound impact of early cancer detection on treatment efficacy and patient survival rates. Achieving this delicate balance is critical to ensure that diagnostic tests effectively identify HBV- or NV-HCC cases at an early stage while minimizing the risks associated with false-positive results, thereby optimizing patient outcomes in clinical practice. Lastly, the integration and standardization of various platforms for measuring gene expression, along with diverse bioinformatics pipelines, are imperative for advancing the development of clinically relevant gene expression-based assays within the clinical setting.
We acknowledge the necessity of further investigation into the mechanistic pathways by which newly discovered biomarkers impact HCC development. Although SH3PXD2B, an adapter protein implicated in the formation of invadopodia and podosomes, as well as extracellular matrix degradation, has been demonstrated to facilitate intravascular and extravascular invasion and metastasis in human colon cancer, breast cancer, and melanoma cells, its role in regulating HCC remains unexplored [9]. Interestingly, suppression of SH3PXD2B impedes both the formation and functionality of invadopodia, as well as the invasive properties of Hep3B cells [9], which harbor an integrated HBV genome. These findings suggest a potential role in facilitating the invasion and metastasis of HCC. Moreover, the expression of SH3PXD2B correlates with a higher rate of HBV infection and shorter overall survival and recurrence-free survival in patients with HCC [9]. These associations underscore its potential as a prognostic biomarker for HCC, rather than solely as a diagnostic biomarker for HBV-HCC, as revealed by our study.
The immune checkpoint molecule CD70, a potent blood-based biomarker for NV-HCC diagnosis revealed by our study, is a ligand of CD27, where the involvement of the CD70-CD27 axis is increasingly being investigated in hematological and solid malignancies [10]. In HCC, while exact mechanism of CD70 expression in tumor cells remains unknown, recent evidence implicates the epigenetic dysregulation of this gene as evidenced by the hypomethylation of CD70 promoter and dominant CD70 expression in the tumor areas compared with the adjacent nontumor areas of HCC patients [11]. Interestingly, depletion of MEF2D, which binds to the promoter region of the CD70 gene and promotes its transcription, in HCC cells injected into immunocompetent mice, along with the use of a CD70 blocking antibody, resulted in diminished immunosuppressive function of Tregs and heightened T cell-mediated anti-tumor immune responses [12]. Taken together, these findings indicate that modulation of the CD70-CD27 signaling axis could enhance the effectiveness of immune therapies for HCC.
Given the urgent need to detect early-stage tumors and refine patient stratification for HCC surveillance [13], the utilization of multiomics approaches, which are increasingly employed [14,15], to identify biomarkers linked to both HBV and non-viral causes of HCC, would not only enhance our comprehension of the disease’s pathogenesis but also enable the development of improved personalized diagnostic and therapeutic strategies.

ACKNOWLEDGMENTS

We acknowledge support provided by the National Research Foundation (NRF) of Korea (2020M3A9D8037604, 2020R1A6A1A03043539, 2022R1A2C1008793, 2022R1C1 C1004756, and 2021R1C1C1009619, RS-2024-0039997) and the Korea Health Technology R&D Project of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1734).

FOOTNOTES

Authors’ contribution
S.B.L. and H.J.C. drafted and approved the manuscript.
Conflicts of Interest
The authors have no conflicts to disclose.

Abbreviations

HCC
hepatocellular carcinoma
HBV
hepatitis B virus
NV-HCC
nonviral HCC
ICI
immune checkpoint inhibitors

REFERENCES

1. Ahn JC, Yang JD. Unveiling etiology-specific blood biomarkers in hepatocellular carcinoma: A gateway to personalized medicine: Editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”. Clin Mol Hepatol 2024;30:689-691.
crossref pmid pdf
2. Hong J, Eun JW, Baek GO, Cheong JY, Park S, Kim SS, et al. Multiomics profiling of buffy coat and plasma unveils etiologyspecific signatures in hepatocellular carcinoma. Clin Mol Hepatol 2024;30:360-374.
crossref pmid pmc pdf
3. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 2020;38:193-202.
crossref pmid
4. Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, et al. Pembrolizumab versus placebo as second-line therapy in patients from Asia with advanced hepatocellular carcinoma: A randomized, double-blind, phase III trial. J Clin Oncol 2023;41:1434-1443.
crossref pmid pmc
5. Zheng Q, Sun Q, Yao H, Shi R, Wang C, Ma Z, et al. Single-cell landscape identifies the immunophenotypes and microenvironments of HBV-positive and HBV-negative liver cancer. Hepatol Commun 2024;8:e0364.
crossref pmid pmc
6. Diniz MO, Schurich A, Chinnakannan SK, Duriez M, Stegmann KA, Davies J, et al. NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner. Sci Transl Med 2022;14:eabi4670.
crossref pmid
7. Sogbe M, Bilbao I, Marchese FP, Zazpe J, De Vito A, Pozuelo M, et al. Prognostic value of ultra-low-pass whole-genome sequencing of circulating tumor DNA in hepatocellular carcinoma under systemic treatment. Clin Mol Hepatol 2024;30:177-190.
crossref pmid pmc pdf
8. Lim SB, Tan SJ, Lim WT, Lim CT. An extracellular matrix-related prognostic and predictive indicator for early-stage nonsmall cell lung cancer. Nat Commun 2017;8:1734.
crossref pmid pmc pdf
9. Kui X, Wang Y, Zhang C, Li H, Li Q, Ke Y, et al. Prognostic value of SH3PXD2B (Tks4) in human hepatocellular carcinoma: a combined multi-omics and experimental study. BMC Med Genomics 2021;14:115.
crossref pmid pmc pdf
10. Flieswasser T, Van den Eynde A, Van Audenaerde J, De Waele J, Lardon F, Riether C, et al. The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res 2022;41:12.
crossref pmid pmc pdf
11. Dong MP, Thuy LTT, Hoang DV, Hai H, Hoang TH, Sato-Matsubara M, et al. Soluble immune checkpoint protein CD27 is a novel prognostic biomarker of hepatocellular carcinoma development in hepatitis C virus-sustained virological response patients. Am J Pathol 2022;192:1379-1396.
crossref pmid
12. Kong F, Wang L, Ye Q, Xiong Y, Hancock WW. Abstract 5629: MEF2D regulates T cell function via the CD70-CD27 signaling axis and promotes immune escape in hepatocellular carcinomas. Cancer Res 2024;84(6 Suppl):5629.
crossref pdf
13. Sohn W, Paik YH. Correspondence on Editorial regarding “Impact of nationwide hepatocellular carcinoma surveillance on the prognosis in patients with chronic liver disease”. Clin Mol Hepatol 2023;29:182-184.
crossref pmid pmc pdf
14. Lee SH, Jang HJ. Deep learning-based prediction of molecular cancer biomarkers from tissue slides: A new tool for precision oncology. Clin Mol Hepatol 2022;28:754-772.
crossref pmid pmc pdf
15. Oh S, Baek YH, Jung S, Yoon S, Kang B, Han SH, et al. Identification of signature gene set as highly accurate determination of metabolic dysfunction-associated steatotic liver disease progression. Clin Mol Hepatol 2024;30:247-262.
crossref pmid pmc pdf

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: cmh_journal@ijpnc.com
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 1358
TOTAL : 2174015
Close layer