Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC

Abstract

Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells' metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.

Keywords: T cells exhaustion; hepatocellular carcinoma (HCC); immune cell; metabolism; mitochondria.

Figure 1

Mitochondrial quality control of T cells on immunometabolism. Immune cell differentiation and function are crucially dependent on specific metabolic programs dictated by mitochondria and the specific processes that occur in mitochondria are intimately linked to their morphology that is shaped by biogenesis, fusion and fission events, and mitophagy. In addition, mitochondria transfer also is regarded as a means of quality control that happens from cell to cell. They receive different signals from external stimuli that dynamically maintain the quality of the mitochondria in the cell to maintain normal energy metabolism. Mitochondrial transfer, in particular, occurs when mitochondria are damaged and unable to maintain normal function, and inevitably affects the mass of intracellular mitochondria.

Figure 2

Intercellular mitochondrial transfer modes. There are four major transfer modes, such as extracellular vehicles (EVs), cell fusion, gap junction connections (GJCs), tunneling nanotube (TNTs)under the stimulation of stress reaction, inflammation response, DNA damage, and increased interstitial ROS levels. TNTs are the common type of cellular community which could transform the metabolism and functional features of the recipient cells, and the initial increase in mitochondrial mass could reveal between the donor and recipient cells. A high level of ROS in mitochondrial recipient cells can trigger activation of p53 and the downstream Akt/PI3K/mTOR axis, resulting in an overexpression of M-sec, which could enhance TNT formation.

Figure 3

Exhausted T cell with depleted mitochondria in hepatocellular carcinoma genesis and progression. When the tumor or viral antigen is correctly recognized, the T cell immune response rapidly expands and differentiates to perform the corresponding immune function. However, under chronic antigenic stimulation, such as after HBV infection, a dysfunctional phenomenon called “exhaustion” limits the antiviral response and affects the subsequent antitumor response, which happens in immune cells with dysfunctional mitochondria. Damaged mitochondria are unable to maintain the demands of continuous immune metabolism, resulting in T cell exhaustion - loss of self-renewal and continuous differentiation.