Table 2.
Mechanisms responsible for altered functions of immune cells in obesity-related HCC.
| Cells | Tendency in obesity-related HCC | Mechanisms | References |
|---|---|---|---|
| Immune Effector Cells | |||
| CD8+ T cells | Suppressed | Metabolic shift from OXPHOS to glycolysis reduces reliance of CD8+ T cells on oxygen but makes them become more sensitive to glucose deprivation in TIME. Obesity also impairs T cell compartment and induces T cells exhaustion. | (73–78) |
| CD4+ T cells | Suppressed | Although elevated circulating CD4+ T cells are induced by leptin, CD4+ T cells display increased expression of exhaustion markers. CD4+ T cells possess greater mitochondrial mass when compared to CD8+ T cells and could be easily impaired by lipid-induced ROS burst. | (78–82) |
| B cells | Suppressed | B cell activation facilitates NAFLD/NASH progression and thus HCC. During obesity, adipocytes promote MDSCs development and inhibit B lymphopoiesis. Persistent inflammation hampers response of B cells to antigens and accelerate age defects in B cells. Increased lipolysis facilitates Bregs survival and thus immunosuppression. | (83–92) |
| NK cells | Paradoxical | Lipid deposition and aberrant lipid metabolism lead to senescence of iNKT in the TIME. Metabolic shift based on lipid-rich environment further hampers functions of NK cells. However, cholesterol accumulation in NK cells may also stimulates effector functions and thus inhibits HCC progression. | (93–96) |
| Immunosuppressive Cells | |||
| MDSCs | Paradoxical | MDSCs undergo metabolic shift from aerobic glycolysis to FAO in lipid-rich environment to increase the utilization of FA, thus meeting high energy demand and sustaining suppressive function in TIME. Cholesterol accumulation also enhances functions of MDSCs, but its derivatives block MDSCs survival and abundance. | (97–100) |
| TAMs | Enhanced | In glucose-rich environment such as hyperglycemia, TAMs possess upregulated GLUT1 expression, thus enhancing their glycolysis and immunosuppressive functions. In low glucose but lipid-rich environment such as obesity-related TME, TAMs take full advantage of fatty acids to maintain immunosuppressive functions. | (101–106) |
| Tregs | Paradoxical | Although obese populations exhibit diminished frequency of Tregs, intratumoral Tregs can be distinct with peripheral Tregs. In lipid-rich environment, intratumoral Tregs upregulate their surface FA transporter CD36 and show a tendency towards FAO, thus meeting biomass demands and exhibiting resistance to lipotoxicity. | (107, 108) |