‘Invisible’ immune checkpoint molecule causing resistance to anti-PD1 therapy in HCC

Greten, Tim F.

doi:10.1136/gutjnl-2022-329099

Cited by 1 publication

(1 citation statement)

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“…GO analysis was used to elucidate the underlying mechanism of the FGFR signaling blockade, and the main mechanism was found to be the inhibition of metabolic pathway signaling. Zhewen et al showed that higher baseline PPARγ expression was associated with poorer survival of ICI-treated patients in multiple cancer types [ 34 ]. The depletion of energy (e.g., lipid and glucose) in TIME is known to promote the formation of an immune cold environment, especially affecting T cell function such as exhausting [ 35 – 37 ].…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma

Suzuki,

Iwamoto,

Tanaka

et al. 2023

Hepatol Int

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Background & aims Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME). Methods We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database. Results The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells. Conclusions In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

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Section: Discussionmentioning

confidence: 99%