Cancer immunology, immunotherapy : CII · 2025
High-plex imaging of hepatoblastoma and adjacent liver in pediatric patients reveals a predominant myeloid infiltrate expressing immune-checkpoints.
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Krijgsman Daniëlle, Schubert Stephanie A, Kraaier Lianne J, Lu Yuyan, van Avondt Kristof, Verdonschot Meggy E L, Leusen Jeanette H W, van den Heuvel Marius C, de Kleine Ruben H, de Meijer Vincent E, Kraal Kathelijne C J, de Krijger Ronald R, Zsiros József, Peng Weng Chuan, Vercoulen Yvonne
Аннотация
BACKGROUND AND AIMS: Hepatoblastoma (HB) is a rare form of pediatric liver cancer currently treated with chemotherapy, which has major side effects, and surgery. We aimed to characterize the immune landscape of HB to improve our understanding of the immunologic contribution to this disease and explore immunotherapeutic options.
METHODS: To investigate the tissue landscape, a high-plex imaging mass cytometry panel was developed and applied to tissue of treatment-naïve HB and chemotherapy-treated HB, with paired adjacent normal liver tissue. Moreover, immunofluorescence was used to stain HB and normal liver tissue for the Kupffer cell marker MARCO, macrophage markers CD68 and CD163, T cell marker CD8, and immune checkpoints VISTA and SIRPα. A public single-cell RNA sequencing (scRNA-seq) dataset was analyzed consisting of chemotherapy-treated HB and paired normal liver tissue.
RESULTS: Normal liver tissue showed a compartmentalized immune landscape between the portal triad area and liver parenchyma. HB showed a heterogeneous immune landscape predominantly comprising CD68+CD163+ macrophages with expression of immune checkpoints SIRPα, and VISTA, whereas the number of T cells was limited. These findings were confirmed with immunofluorescence in a second cohort. Transcriptome profiling demonstrated that tumor-associated macrophages, characterized by low MARCO expression, showed upregulated inflammatory markers. In addition, an early activated phenotype of CD8+ T cells in chemotherapy-treated HB and the absence of an exhaustion signature and immune checkpoint expression was observed.
CONCLUSIONS: The absence of immune checkpoints and exhaustion markers in CD8+ T cells prohibits T cell-targeting by immune checkpoint blockade in HB patients. Instead, HB tissue contains a large myeloid compartment expressing myeloid checkpoints VISTA and SIRPα. This could provide opportunities for macrophage targeting and promote the development of improved treatment strategies for HB patients.
METHODS: To investigate the tissue landscape, a high-plex imaging mass cytometry panel was developed and applied to tissue of treatment-naïve HB and chemotherapy-treated HB, with paired adjacent normal liver tissue. Moreover, immunofluorescence was used to stain HB and normal liver tissue for the Kupffer cell marker MARCO, macrophage markers CD68 and CD163, T cell marker CD8, and immune checkpoints VISTA and SIRPα. A public single-cell RNA sequencing (scRNA-seq) dataset was analyzed consisting of chemotherapy-treated HB and paired normal liver tissue.
RESULTS: Normal liver tissue showed a compartmentalized immune landscape between the portal triad area and liver parenchyma. HB showed a heterogeneous immune landscape predominantly comprising CD68+CD163+ macrophages with expression of immune checkpoints SIRPα, and VISTA, whereas the number of T cells was limited. These findings were confirmed with immunofluorescence in a second cohort. Transcriptome profiling demonstrated that tumor-associated macrophages, characterized by low MARCO expression, showed upregulated inflammatory markers. In addition, an early activated phenotype of CD8+ T cells in chemotherapy-treated HB and the absence of an exhaustion signature and immune checkpoint expression was observed.
CONCLUSIONS: The absence of immune checkpoints and exhaustion markers in CD8+ T cells prohibits T cell-targeting by immune checkpoint blockade in HB patients. Instead, HB tissue contains a large myeloid compartment expressing myeloid checkpoints VISTA and SIRPα. This could provide opportunities for macrophage targeting and promote the development of improved treatment strategies for HB patients.