Dear Editor,
We appreciate the insightful and constructive comments from Glenn Deng and Kejun Yan regarding our study, which described infiltrative morphology (type IV) as a distinct molecular and clinical subtype of hepatocellular carcinoma (HCC) associated with resistance to atezolizumab plus bevacizumab (Ate/Bev) [
1,
2]. We would like to address their three key points.
First, we agree that the molecular features observed in infiltrative HCC, such as TP53/ATM loss-of-function mutations and activated TGF-β signaling pathways, likely represent a combination of intrinsic tumor drivers and extrinsic microenvironmental pressures. Given that our multi-omics analysis was based on bulk tumor tissue, the contribution of a pre-existing fibro-inflammatory liver microenvironment cannot be fully disentangled [
3]. Accordingly, rather than defining these features as purely tumor-cell-intrinsic, we concur that they should be interpreted as molecular signals co-shaped by the interaction between the tumor and its microenvironment. Furthermore, we fully agree that future spatial transcriptomics and single-cell analyses will be essential to dissect these functional interactions.
Second, to further assess the robustness of infiltrative morphology as an independent predictor, we conducted additional analyses incorporating genomic and host-related variables [
4,
5]. Regarding tumor mutational burden (TMB), data were available for 53 patients with values from 1 to 12 in our cohort, and were evaluated according to gross type [
6]. We observed a trend toward lower TMB in infiltrative HCC (
P=0.015 and
Fig. 1A), but no clear association between TMB and clinical outcomes was observed in univariable analysis (
P>0.05). These findings suggest that infiltrative morphology is unlikely to merely represent a radiographic surrogate of a low-immunogenicity state. Nevertheless, given the limited number of patients with available TMB data in our cohort, further validation in larger studies will be required to more definitively clarify the role of TMB in this subtype. Furthermore, we evaluated the prognostic nutritional index (PNI) and the neutrophil-to-lymphocyte ratio (NLR) to account for host systemic factors [
7,
8]. We observed that patients with infiltrative HCC had lower PNI and higher NLR compared to those with non-infiltrative HCC, confirming a worse baseline host status in this subtype (
Fig. 1B). Importantly, in multivariable models, the infiltrative morphology remained a robust and independent predictor of poor prognosis even after adjusting for PNI or NLR. Notably, while PNI did not retain statistical significance in the multivariable analysis, NLR remained an independent prognostic factor (
Fig. 1C, 1D). These findings demonstrate that although host systemic inflammation is an important contributor to prognosis, the infiltrative morphology itself reflects a distinct biological aggressiveness that independently drives poor clinical outcomes. We fully agree that future studies incorporating more integrated scoring systems will be essential to further unravel the complex interplay between tumor morphology and host-related factors.
Finally, we would like to emphasize that our findings should not be generalized to suggest resistance to all immunotherapies. Rather, they indicate that Ate/Bev alone may be insufficient to elicit an adequate therapeutic response in infiltrative HCC. Inhibition of the PD-1/PD-L1 axis by atezolizumab may be insufficient to fully activate antitumor immunity if alternative immune checkpoints, such as CTLA-4, remain functionally active. In parallel, our data suggest that VEGF inhibition with bevacizumab, while capable of vascular modulation, may be insufficient to eradicate the immunosuppressive microenvironment characterized by persistent regulatory T cells and suppressive myeloid subsets in infiltrative HCC. Therefore, these findings should not be interpreted to exclude patients with infiltrative HCC from subsequent immunotherapeutic approaches after Ate/Bev failure. Rather, the infiltrative morphology may provide a rationale for considering alternative or additive strategies targeting non-overlapping immune mechanisms. Notably, recent evidence suggests that nivolumab plus ipilimumab may provide clinical benefit in patients with advanced HCC who experience disease progression after Ate/Bev [
9]. Mechanistically, ipilimumab can diminish intratumoral regulatory T cells (Tregs) and facilitate de novo T cell priming, thereby alleviating liver-specific immune tolerance and promoting intrahepatic immune responsiveness [
10]. These effects may translate into improved antitumor efficacy in patients who do not derive benefit from prior Ate/Bev. In this context, the high expression of intratumoral Tregs observed in infiltrative HCC with poor response to Ate/Bev in our study provides a plausible rationale for considering CTLA-4–targeting regimens in this subtype, as depletion of Tregs by ipilimumab may partially overcome the immunosuppressive microenvironment and restore antitumor immunity.
In conclusion, by delineating the interactions between tumor-intrinsic alterations and the hepatic microenvironment, and by incorporating host inflammatory markers into prognostic assessment, we defined infiltrative HCC as a highrisk subtype with unique therapeutic implications. This integrative framework provides a foundation for developing precision therapies targeting infiltrative HCC.
FOOTNOTES
-
Authors’ contributions
Won Suk Lee and Seonjeong Woo conducted the data analysis and wrote the manuscript.
Sohyun Hwang, Chan Kim and Hong Jae Chon revised the manuscript.
-
Acknowledgements
This research was funded by National Research Foundation of Korea (NRF) grants supported by the Korean government (MSIT) (grant number: NRF-2023R1A2C2004339). This research was supported by a grant of the Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00438843). This research was supported by Basic Science Research Program through NRF funded by the Ministry of Education (grant number: RS-2019-NR040073).
-
Conflicts of Interest
Hong Jae Chon has received speaker honoraria from Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Sanofi, Servier, AstraZeneca, and Boryung; he is a consultant/ advisory board member for Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Servier, AstraZeneca, Boryung, IMBDx, and Aptamer Science; he received grants from Roche, BeiGene, IMBDx, Dong-A ST, and Boryung. Chan Kim is involved in consulting or advisory capacities with Roche, ONO, MSD, BMS, Oncocross, and Virocure, and has received research funding from Boryung Pharmaceuticals, Oncocross, SillaJen, and Virocure. The remaining authors declare no potential conflicts of interest.
Figure 1.Association between infiltrative morphology and host systemic factors in patients with HCC. Box plots showing (A) TMB, (B) the PNI, and the NLR across gross types. TMB was evaluable in 53 patients, whereas the PNI and the NLR were assessed in 302 patients for whom lymphocyte data were available. Among type I, II, III, and IV HCC, trends were evaluated using the Jonckheere-Terpstra trend test. (C and D) Results of the multivariable Cox regression analysis of gross type and clinical factors for PFS and OS in 302 patients with advanced HCC, incorporating (C) PNI or (D) NLR as covariate. HCC, hepatocellular carcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein; PVTT, portal vein tumor thrombosis; PNI, prognostic nutritional index; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PFS, progression-free survival; TMB, tumor mutational burden.
Abbreviations
atezolizumab plus bevacizumab
neutrophil-to-lymphocyte ratio
prognostic nutritional index
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