Journal for immunotherapy of cancer · 2026
Systemic immune profiling uncovers divergent mechanisms and predictive biomarkers of response to combination immunotherapies in hepatocellular carcinoma.
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Nishio Akira, Kodama Takahiro, Daiku Kazuma, Maesaka Kazuki, Tanaka Satoshi, Nozaki Yasutoshi, Kurahashi Tomohide, Matsumoto Kengo, Nawa Takatoshi, Tawara Seiichi, Tokuda Yuki, Nakabori Tasuku, Sakamori Ryotaro, Ohkawa Kazuyoshi, Miyazaki Masanori, Yamamoto Shuhei, Shigeno Satoshi, Myojin Yuta, Tahata Yuki, Hikita Hayato, Takehara Tetsuo
Аннотация
BACKGROUND: Combination immunotherapies such as atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) improve outcomes in advanced hepatocellular carcinoma (HCC), yet systemic immune mechanisms underlying response remain incompletely defined.
METHODS: We performed single-cell RNA sequencing with CITE-seq on peripheral blood mononuclear cells from 19 advanced HCC patients (Atez/Bev: 5 responders (R), 5 non-responders (NR); Dur/Tre: 4 R, 5 NR) before and during treatment, yielding 345 962 single-cell transcriptomes spanning 22 immune cell clusters. Analysis included transcriptional profiling, gene set enrichment analysis, T cell receptor (TCR) repertoire analysis, and CellChat-based intercellular communication modeling.
RESULTS: Baseline comparisons revealed distinct systemic immune states by etiology: non-viral HCC exhibited CD8+ T cells with heightened cytotoxic and memory-associated signatures. Under Atez/Bev, CD14+ monocytes in responders were reprogrammed toward antigen-presenting and lymphocyte-supporting functions, while PRKCH+ NK cells acquired a robust cytotoxic program reinforced by monocyte-NK interactions via ICAM-integrin and HLA-E-NKG2C axes. In contrast, Dur/Tre responders exhibited CD14+ monocyte programs enriched in inflammatory and interferon-driven antigen presentation, alongside transcriptional reprogramming of CD8+ central memory T cells into an effector-ready state with strong crosstalk to monocytes. TCR analysis revealed regimen-specific differences: clonotype expansion occurred irrespective of response under Atez/Bev, whereas Dur/Tre responders showed both clonotype expansion and higher pretreatment CD8+ T cell diversity, with expanded clones displaying cytotoxic and interferon-responsive profiles. Pretreatment immune composition, including naïve CD4+ T cells and PRKCH+ NK cells for Atez/Bev and conventional dendritic cells for Dur/Tre, also predicted response.
CONCLUSIONS: Our findings reveal regimen-specific systemic immune mechanisms in advanced HCC: Atez/Bev amplifies monocyte-NK cytotoxic axes, whereas Dur/Tre enhances monocyte-T cell inflammatory networks and TCR repertoire diversity. These insights highlight distinct predictive biomarkers and support regimen-tailored immunotherapy in HCC.
METHODS: We performed single-cell RNA sequencing with CITE-seq on peripheral blood mononuclear cells from 19 advanced HCC patients (Atez/Bev: 5 responders (R), 5 non-responders (NR); Dur/Tre: 4 R, 5 NR) before and during treatment, yielding 345 962 single-cell transcriptomes spanning 22 immune cell clusters. Analysis included transcriptional profiling, gene set enrichment analysis, T cell receptor (TCR) repertoire analysis, and CellChat-based intercellular communication modeling.
RESULTS: Baseline comparisons revealed distinct systemic immune states by etiology: non-viral HCC exhibited CD8+ T cells with heightened cytotoxic and memory-associated signatures. Under Atez/Bev, CD14+ monocytes in responders were reprogrammed toward antigen-presenting and lymphocyte-supporting functions, while PRKCH+ NK cells acquired a robust cytotoxic program reinforced by monocyte-NK interactions via ICAM-integrin and HLA-E-NKG2C axes. In contrast, Dur/Tre responders exhibited CD14+ monocyte programs enriched in inflammatory and interferon-driven antigen presentation, alongside transcriptional reprogramming of CD8+ central memory T cells into an effector-ready state with strong crosstalk to monocytes. TCR analysis revealed regimen-specific differences: clonotype expansion occurred irrespective of response under Atez/Bev, whereas Dur/Tre responders showed both clonotype expansion and higher pretreatment CD8+ T cell diversity, with expanded clones displaying cytotoxic and interferon-responsive profiles. Pretreatment immune composition, including naïve CD4+ T cells and PRKCH+ NK cells for Atez/Bev and conventional dendritic cells for Dur/Tre, also predicted response.
CONCLUSIONS: Our findings reveal regimen-specific systemic immune mechanisms in advanced HCC: Atez/Bev amplifies monocyte-NK cytotoxic axes, whereas Dur/Tre enhances monocyte-T cell inflammatory networks and TCR repertoire diversity. These insights highlight distinct predictive biomarkers and support regimen-tailored immunotherapy in HCC.