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bioRxiv · 10.1101/2023.06.28.546852

Hepatoblastoma exhibits a predominantly myeloid immune landscape and reveals opportunities for macrophage targeted immunotherapy

Krijgsman, D.·Kraaier, L.·Verdonschot, M.·Schubert, S.·Leusen, J.·Duiker, E.·de Kleine, R.·de Meijer, V.·de Krijger, R.·Zsiros, J.·Peng, W. C.·Vercoulen, Y.
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Abstract

Background & AimsHepatoblastoma (HB) is a rare form of pediatric liver cancer which is currently treated with chemotherapy and surgery. The side effects of chemotherapy pose a major problem in HB and underline the need for an alternative treatment option. We aimed to characterize the immune landscape of HB to improve our understanding of the immunologic contribution to this disease and explore immunotherapeutic options. MethodsAn imaging mass cytometry panel of 36 antibodies was used on tissue of treatment-naive HB (n=5), and chemotherapy-treated HB (n=3), with paired distal normal liver tissue. Immunofluorescence was used to stain HB and normal liver tissue for Kupffer cell marker MARCO. A public single-cell RNA-sequencing (scRNA-seq) dataset was analyzed consisting of 9 chemotherapy-treated HB and paired normal liver tissue. ResultsHB showed a heterogeneous immune landscape predominantly comprising macrophages and monocytes with high expression of immune checkpoints CD47, SIRP, and VISTA, whereas T cells were limited. Chemotherapy increased influx of macrophages and CD8+ T cells in HB. Transcriptome profiling demonstrated an early activated phenotype of CD8+ T cells in chemotherapy-treated HB and absence of an exhaustion signature and immune checkpoint expression. Furthermore, tumor-associated macrophages had low MARCO expression, upregulated inflammatory markers and a high liver tissue residency score while expressing other Kupffer cell markers, such as CD5L, to a variable degree. ConclusionsThe absence of immune checkpoints and exhaustion markers in CD8+ T cells prohibits T cell-targeting by immune checkpoint blockade in HB patients. Instead, HB tumors contain a large myeloid compartment which provide opportunities for macrophage targeting, thereby paving the way for the development of improved treatment strategies for HB patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/546852v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@3748e2org.highwire.dtl.DTLVardef@191f9d9org.highwire.dtl.DTLVardef@aa4172org.highwire.dtl.DTLVardef@1aed5f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Krijgsman, D., Kraaier, L., Verdonschot, M., Schubert, S., Leusen, J., Duiker, E., de Kleine, R., de Meijer, V., de Krijger, R., Zsiros, J., Peng, W. C., Vercoulen, Y.. 2023-06-28. Hepatoblastoma exhibits a predominantly myeloid immune landscape and reveals opportunities for macrophage targeted immunotherapy. https://doi.org/10.1101/2023.06.28.546852

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