Dear Editor,
We would like to thank Dr. Kanzaki and Dr. Hoshida for their insightful commentary on our recent study [
1], which introduced the “immune signature score with 10 genes (ISS10)” as a predictive model for response to combination immunotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma (HCC) [
2]. As highlighted by Dr. Kanzaki and Dr. Hoshida, while immune checkpoint inhibitors (ICIs) have introduced new therapeutic avenues for patients with unresectable advanced HCC, the objective response rates remain modest [
3,
4]. Our study sought to address this critical issue by validating the ISS and its refined version, ISS10, to serve as predictive biomarkers that could help stratify patients based on their likelihood of responding to combination therapies. We appreciate their recognition of the clinical potential of ISS10. By reducing the original 105-gene signature to 10 genes, our aim was to create a streamlined, yet powerful, tool that retains its predictive accuracy while minimizing the logistical and economic barriers to its application in clinical practice. Our analysis demonstrated that patients with high-ISS10 scores experienced improved response rates and overall survival when treated with the combination of atezolizumab and bevacizumab, underscoring ISS10’s utility in guiding therapeutic decisionmaking.
We also agree with the important point raised regarding the need for validation across more diverse patient populations, as highlighted by Dr. Kanzaki and Dr. Hoshida. The heterogeneity in liver disease etiology, particularly the distinctions between viral hepatitis-associated HCC and metabolic dysfunction-associated steatotic liver disease (MASLD), is a critical factor that may influence the tumor immune microenvironment and, consequently, treatment response [
5]. To date, our dataset is primarily derived from cohorts with a high proportion of Asian patients and those with viral hepatitis-related HCC, emphasizing the necessity of validating ISS10 in non-Asian populations and in HCC patients with MASLD.
Emerging technologies are revolutionizing our understanding of HCC and its treatment. The integration of cutting-edge single cell resolution technologies, such as spatial transcriptomics and proteomics promises to unravel the intricate tumor biology and immune-tumor interactions within the complex milieu of the tumor microenvironment and underlying liver pathology [
6]. These tools enable us to construct immune signatures at unprecedented cellular detail, providing crucial insights into the mechanisms driving immunotherapy responses in HCC. Complementing these advances, personalized cancer vaccines targeting tumorspecific neoantigens have shown potential in amplifying immune responses [
7]. This approach, coupled with singlecell biomarker discovery, could provide additional layers of patient-specific data, further refining our ability to predict immunotherapy outcomes. These advanced techniques will allow us to define immune signatures at a cellular level, offering a more precise understanding of how immune-oncologic interactions drive treatment responses in HCC. Additionally, the rise of non-invasive technologies, including liquid biopsy for circulating tumor molecules, holds great potential for translating these insights into real-world clinical settings [
8]. Liquid biopsy may provide a practical means to assess tumor molecular profiles and stratify patients for immunotherapy, making it an invaluable tool for real-time monitoring of treatment responses, especially in the absence of tumor tissue.
The logistical challenges associated with tumor tissue acquisition are also valid concerns, particularly in the context of systemic therapies for advanced-stage HCC. However, as Dr. Kanzaki and Dr. Hoshida noted, tissue acquisition may be less of a barrier in the setting of adjuvant therapy. We are optimistic that as technologies for less invasive tissue sampling improve, the utility of biomarkers will expand beyond its current scope, making it feasible for broader clinical application.
Once again, we deeply appreciate the thoughtful feedback from Dr. Kanzaki and Dr. Hoshida. Their comments emphasize important directions for future research, particularly in validating ISS10 across diverse populations and leveraging new technologies for precision biomarker discovery. We remain committed to advancing this field to improve outcomes for patients with advanced HCC through refined and personalized immunotherapeutic strategies.
ACKNOWLEDGMENTS
This work is supported by the NIH/NCI under award numbers R01CA237327, P50CA217674, and P30CA016672; The University of Texas MD Anderson Cancer Center Institutional Research Grant (IRG) Program; The University of Texas MD Anderson Cancer Center Institutional Bridge Funds; the Duncan Family Institute for Cancer Prevention and Risk Assessment Seed Funding Research Program at MD Anderson Cancer Center.
FOOTNOTES
-
Authors’ contribution
Conception and design of the work: Sung Hwan Lee, Ju-Seog Lee. Drafting the article: Sung Hwan Lee, Sun Young Yim, Ju-Seog Lee. Critical revision of the article: All authors.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
immune checkpoint inhibitors
immune signature score with 10 genes
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 1. Kanzaki H, Hoshida Y. Transcriptomic signature in advanced hepatocellular carcinoma tissue to predict combination immunotherapy response: Editorial on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”. Clin Mol Hepatol 2025;31:308-310.
- 2. Yim SY, Lee SH, Baek SW, Sohn B, Jeong YS, Kang SH, et al. Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial. Clin Mol Hepatol 2024;30:807-823.
- 3. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 2022;1:EVIDoa2100070.
- 4. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
- 5. Wang H, Tsung A, Mishra L, Huang H. Regulatory T cell: a double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma. EBioMedicine 2024;101:105031.
- 6. Vandereyken K, Sifrim A, Thienpont B, Voet T. Methods and applications for single-cell and spatial multi-omics. Nat Rev Genet 2023;24:494-515.
- 7. Yarchoan M, Gane EJ, Marron TU, Perales-Linares R, Yan J, Cooch N, et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat Med 2024;30:1044-1053.
- 8. Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223-238.
Citations
Citations to this article as recorded by
- Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
Hiroaki Kanzaki, Yujin Hoshida
Clinical and Molecular Hepatology.2025; 31(1): e121. CrossRef
