Crosstalk between metabolism, redox homeostasis and regulatory T cell function in hepatocellular carcinoma

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.