Immunotherapeutic response in liver cancer can be predicted by new method

Researchers are looking to improve immunotherapy for liver cancer or hepatocellular carcinoma (HCC). Although immunotherapy has become the standard treatment method for HCC, its response rate has only been around 30% in patients with advanced disease. Now researchers at Osaka University report that they have developed an analytical method that could help predict whether a patient with HCC would respond successfully to immunotherapy.

The results, “Multiomics identifies link between intratumoral steatosis and depleted tumor immune microenvironment in hepatocellular carcinoma», are published in the journal Hepatology.

“Immunotherapy has become the standard treatment for HCC, but its effectiveness remains limited,” the researchers wrote. “To identify immunotherapy-responsive HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC.”

TIME is the area inside the tumor in which various immune cells and other cell types interact and send/receive messages and signals.

“We looked at 113 patients who developed HCC without hepatitis virus infection,” said Hiroki Murai, the study’s lead author. “We used a multi-omics approach, which means we looked at the DNA sequences of specific genes frequently mutated in HCC, but also performed a more general assessment of RNA sequences to study expression levels. of all the genes in these tumors.”

The researchers categorized the 113 HCC cases based on their TIME composition estimated by gene expression profiling. They found a single TIME in 23% of HCC cases that had a significant amount of intratumoral fat accumulation, known as steatotic HCC.

“Steatotic HCC tumors tended to have an immuno-enriched, but immuno-depleted TIME,” explained lead author Tetsuo Takehara. “There was a strong infiltration of immune cells, including M2 macrophages and cancer-associated fibroblasts, but nearby T cells were depleted. They have lost much of their combat capability.

The group also determined that increased fat levels in these tumor cells induce the expression of PD-L1, an immune checkpoint molecule that leads to immunosuppressive TIME.

“An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of co-cultured macrophages and fibroblasts,” wrote noted the researchers. “Patients with steatotic HCC, confirmed by chemical shift MRI, had significantly longer PFS with combination immunotherapy using anti-PD-L1 and anti-VEGF antibodies.”

“PD-L1 is a common target for immunotherapy drugs because interfering with this protein can help restore immune cell functions,” says Takahiro Kodama, co-lead author of the study. “Our results suggest that HCC tumors with steatosis would therefore be sensitive to these types of drugs.”

The results demonstrate that intratumoral steatosis could be used as a new biomarker to assess the efficacy of immunotherapy in HCC cases.

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