Research by scientists at the German Cancer Research Center (DKFZ), the University Hospital of Tübingen, and Sanford Burnham Prebys Medical Discovery Institute has discovered a key molecular mechanism that drives the growth of liver cancer cells, while simultaneously suppressing the body’s immune response to the tumor. Results from the team’s study, including work in human tissues and experiments in mouse models, identified persistently activated ATF6α as a tumor driver for hepatocellular carcinoma (HCC).
The mechanism, they suggested, is paradoxically also linked to increased sensitization to immune checkpoint blockade (ICB) immunotherapy, and could in the future help identify patients who respond particularly well to such treatment, opening up new therapeutic approaches.
Headed by Mathias Heikenwälder, PhD, at the University of Tübingen and DKFZ, the researchers reported on their results in Nature, in a paper titled “Activated ATF6α is a hepatic tumour driver restricting immunosurveillance,” in which they stated, “Our findings suggest that persistently activated ATF6α is a tumor driver, a potential stratification marker for ICB response, and a therapeutic target for HCC.”
Hepatocellular cancer is particularly difficult to treat and is one of the deadliest cancers worldwide. “Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality, and there are limited therapies,” the authors wrote. “Despite advances in immunotherapies that improved survival, the complex genetic, metabolic, and inflammatory interactions remain a barrier toward effective treatment.”
HCC develops as a result of chronic inflammation and the resulting chronic cell stress, triggered, for example, by metabolic disorders. For example, too many faulty proteins can overload the liver cells, which then try to protect themselves with a stress response. One of the alarm signals that activate this self-protection is the protein ATF6α.
Heikenwälder and colleagues investigated whether activated ATF6α is involved in the development of liver cancer. The researchers analyzed extensive datasets from liver cancer patients and tissue samples from international collections. They found that tumors with high ATF6α activity are more aggressive, grow faster, and are associated with a significantly poorer survival prognosis. At the same time, the immune response in and around these tumors is severely suppressed. “ATF6α activation in human HCC is significantly correlated with an aggressive tumor phenotype, characterized by reduced patient survival, enhanced tumour progression, and local immunosuppression,” they noted.
Cytotoxic T cells, whose task is to recognize and destroy cancer cells, are particularly affected by this immunosuppression. In ATF6α-active tumors, these T cells are numerous but functionally “exhausted.” The cause is a profound metabolic reprogramming of the cancer cells: they consume large amounts of glucose. This robs the immune cells of the nutrients they need to work effectively. “Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoral T cell infiltration, and nutrient-deprived immune exhaustion,” the team further stated.
A key mechanism in this process is suppression of the enzyme FBP1, which normally supports glucose production in the liver and also acts as a tumor suppressor. However, ATF6α blocks the expression of the FBP1 gene, resulting in consequences that include increased sugar breakdown via glycolysis, rising cell stress, and suppression of immune response. Their results, they reported, demonstrated that “… ATF6α-activated hepatocytes exhibit elevated glycolysis, a reduction in crucial nutrients, and an augmented release of lactate into the microenvironment that restricts T cell function.”
“We have discovered that permanent activation of ATF6α does not protect the cell in the long term,” summarized Heikenwälder. “On the contrary, chronic cell stress drives the onset of liver cancer and at the same time creates an environment in which immune cells lose their function.”
In various mouse models, the researchers showed that permanent activation of ATF6α alone is sufficient to trigger chronic liver inflammation and ultimately liver cancer. Conversely, significantly fewer tumors developed when ATF6α was switched off in liver cells. “Targeting Atf6 through germline ablation, hepatocyte-specific ablation, or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models,” they stated.
Pardoxically, despite their immunosuppressive environment, ATF6α-active tumors were shown to respond exceptionally well to immune checkpoint inhibitor (ICI) therapy, which is designed to release the brakes on the immune system, allowing the immune cells to fight the cancer again. In mouse models, ICI therapy drastically reduced tumor burden and prolonged the animals’ survival. The researchers also found that among patients with advanced liver cancer, those with high ATF6α activity were particularly likely to respond completely to immunotherapy. “Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response, they wrote. “… the induction of ATF6α activation in preclinical liver cancer models significantly improved response to anti-PD-1 therapy.”
“ATF6α is a double-edged sword,” said Heikenwälder. “On the one hand, it drives liver cell cancer, but on the other hand, it makes tumors vulnerable to immunotherapies.” Co-study leader Randal J. Kaufmann, PhD, at Sanford Burnham Prebys Medical Discovery Institute, added, “Our findings suggest that ATF6α could be used in clinical trials in two ways: as a therapeutic target and as a stratification marker that predicts which patients will particularly benefit from immune checkpoint therapies.”
In addition, the researchers suggest the findings may help point to new opportunities to specifically influence metabolic pathways in order to strengthen the immune defense against liver cancer. “Our work shows how closely metabolism, cell stress, and immune response are linked,” said Heikenwälder. “This understanding is crucial for further developing personalized therapies for liver cancer.”
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