Liver tumours hijack the body’s own immune-suppressing cells, called regulatory T cells, to protect themselves from attack. These T cells accumulate inside hepatocellular carcinoma (HCC) tumours, and the more there are, the worse patients tend to fare. Yet exactly how the tumour environment keeps these cells alive and functional is poorly understood. This project tackles that gap. The researcher has shown that in patients with chronic liver disease—the main risk factor for HCC—Tregs become dysfunctional and prone to dying. But when HCC develops, the tumour microenvironment reverses those defects, making Tregs resilient again. The key appears to be a signalling pathway called Nrf2, which is highly active in tumour-infiltrating Tregs and keeps them alive. This work will uncover the precise mechanisms by which Nrf2 controls Treg metabolism and survival inside HCC tumours. It will also test whether blocking Nrf2—genetically or with drugs—can boost anti-tumour immunity in preclinical mouse models of HCC. If successful, this fundamental science could reveal a new way to disable the tumour’s shield. That might eventually improve responses to existing immunotherapies, which currently work poorly in HCC, especially when it arises from metabolic liver disease.
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Regulatory T cells (Tregs) are a subset of immune cells dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg development or function result in uncontrolled immune responses and tissue destruction, contributing to the pathogenesis of multiple autoimmune and inflammatory disorders. On the other hand, excessive recruitment and activation of Tregs leads to inadequate immunosurveillance, as seen in cancer. Recent discoveries have demonstrated that metabolic processes, redox homeostasis, and mitochondrial function are critical to sustain Treg homeostasis and function and ensure effective immunoregulation. However, these findings are derived from animal models, and the extent to which the same mechanisms apply to humans needs to be elucidated. Such knowledge would allow the design of novel strategies to either disrupt Treg function (e.g. in cancer) or to boost their activity to re-establish tolerance (e.g. in autoimmunity). A particularly pressing indication is hepatocellular carcinoma (HCC), which has emerged globally as one of the most common and deadly malignancies (third most common cause of cancer deaths worldwide). HCC exhibits a suboptimal response to immune check point inhibitors, particularly when the cancer develops in patients with chronic liver disease (CLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD), which is now the leading cause of HCC in the West. Targeting intra-tumoral Tregs in this setting could overcome the limitations of currently available immunotherapies and drastically improve the prognosis of HCC. The challenge the project addresses Tregs accumulate in large numbers within HCC tumours, which negatively correlates with overall patient survival, suggesting that they are key in suppressing immunosurveillance. However, knowledge on the mechanisms underpinning their fitness/adaptation within the HCC microenvironment is limited. My previous work indicates that in CLD patients Tregs are dysfunctional and prone to apoptosis. This is the result of redox, mitochondrial, and metabolic abnormalities, linked to the deficient activation of the nuclear factor E2-related factor 2 (Nrf2) signalling pathway. When HCC develops, typically in the setting of CLD, the tumour microenvironment reverses the Treg metabolic abnormalities caused by CLD. This process is also dependent on Nrf2, which is highly activated in tumour-infiltrating Tregs and promotes their viability. My current fellowship application seeks to elucidate the exact mechanisms by which Nrf2 regulates the metabolic adaptation of Tregs to the HCC microenvironment. Furthermore, I will determine if the genetic/pharmacological inhibition of Nrf2 enhances anti-tumour immunity in pre-clinical in vivo models of HCC.
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