" Instead, #Hepatoblastoma #tumors contain a large suppressive #myeloid compartment which poses opportunities for targeting. Specifically, therapeutic antibodies
targeting the #tumor antigen #GPC3 to induce ADCP by #macrophages, in combination with myeloid
#ImmuneCheckpointBlockade (#CD47/SIRPa, or VISTA) could be a feasible strategy to explore in future studies"
Krijgsman et al. from Vercoulen lab in the #UMCUtrecht, on #bioRXiv:
https://www.biorxiv.org/content/10.1101/2023.06.28.546852v1
bioRxivHepatoblastoma exhibits a predominantly myeloid immune landscape and reveals opportunities for macrophage targeted immunotherapyBackground & Aims Hepatoblastoma (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.
Methods An 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.
Results HB showed a heterogeneous immune landscape predominantly comprising macrophages and monocytes with high expression of immune checkpoints CD47, SIRPα, 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.
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 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.
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### Competing Interest Statement
Yvonne Vercoulen declares speakers fee from Johnson & Johnson, funding from Galapagos and TigaTx B.V. Jeanette Leusen is scientific founder and shareholder of TigaTx.
* ADCP
: Antibody-dependent cellular phagocytosis
APC
: Antigen presenting cells
BSA
: Bovine serum albumin
CAR
: Chimeric antigen receptor
CL
: Classical
FFPE
: Formalin-fixed paraffin-embedded
GPC3
: Glycoprotein glypical-3
HB
: Hepatoblastoma
HCC
: Hepatocellular carcinoma
ICB
: Immune checkpoint blockade
IF
: Immunofluorescence
IHC
: Immunohistochemistry
IMC
: Imaging mass cytometry
INT
: Intermediate
KC
: Kupffer cell
NC
: Non-classical
P-ERK
: Phosphorylated ERK
PCA
: Principal component analysis
PMC
: Princess Máxima Center
RNA-seq
: RNA sequencing
ROI
: Region of interest
RT
: Room temperature
scRNA-seq
: Single-cell RNA-sequencing
TAM
: Tumor-associated macrophages
TMA
: Tissue microarray
TME
: Tumor microenvironment
UMAP
: Uniform manifold approximation and projection
UMCG
: University Medical Center Groningen
UMCU
: University Medical Center Utrecht
[1]: pending:yes