Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

Table 1 Treatment options for hepatocellular carcinoma by targeting regulatory T cells and relative signaling pathways

Treatment	Targets	Functions	Ref.
CCR4 antagonist	CCR4	Administration of a CCR4 antagonist or N-CCR4-Fc, a neutralizing pseudo-receptor that can block Tregs accumulation in HCC, can enhance therapeutic efficacy to PD-1 blockade and sorafenib	Gao et al[37], 2022
miR-26a	IL6/Stat3 and HGF/c-Met	The suppressive effects of miR-26a on HCC growth and angiogenesis are mediated by targeting IL-6/signal transducer and activator of transcription 3 signaling and HGF/HGFR/c-Met signaling, respectively	Yang et al[65], 2013; Yang et al[66], 2014
GDF15 neutralizing antibody	GDF15/CD48	Inhibiting GDF15 function by a neutralizing antibody can effectively eradicate HCC and promote a tumoricidal immune response in mice	Wang et al[53], 2021
Supplementation of Lactobacillus rhamnosus GG or its culture supernatant	The ratio of Treg and Th17 cells	Supplementation of Lactobacillus rhamnosus GG or its culture supernatant can ameliorate chronic alcohol-induced liver injury by reducing hepatic inflammation, enhancing intestinal barrier integrity, and inducing balance in the ratio of Treg and Th17 cells to reduce alcoholic-induced liver injury	Chen et al[22], 2016; Wang et al[72], 2013; Wang et al[73], 2012
Prohep, a novel probiotic mixture	Gut microbiota and Treg differentiation	Probiotic treatment regulated T-cell differentiation in the gut by reducing Th17 polarization and increasing the differentiation of anti-inflammatory Treg cells, by increasing the abundance of beneficial bacteria, such as Prevotella and Oscillibacter	Li et al[74], 2016
Anti-PD-1 and anti-PD-L1 antibodies	PD-1 and PD-L1	Another study also showed that Treg-mediated inhibition of IFN-γ production and cytotoxicity of CD8 T cells can be partially reduced by anti-PD-1 and anti-PD-L1 antibodies in HCC	Langhans et al[76], 2019
Dual anti-PD-1/VEGFR-2 therapy	VEGFR-2 and PD-1	Dual therapies increased CD8 T cell infiltration and activation, reduced Tregs and infiltration of CCR2+monocytes, as well as the phenotype of tumor-associated macrophages (the M1/M2 ratio) in HCC tissue	Shigeta et al[75], 2020
Anti-CTLA-4 monoclonal antibody	Tregs	Treg depletion-mediated by anti-CTLA-4 monoclonal antibody (clone 9H10) restored the function of tumor antigen-specific CD8 T cells, with a synergistic effect with anti-PD-1 treatment	Lee et al[77], 2020
Resveratrol	Tregs and immunosuppressive cytokines including TGF-β1 and IL-10	Treatment with resveratrol, a natural phenol, can inhibit H22 (a mouse HCC cell line)-induced orthotopic HCC tumor growth via decreasing the frequency of CD8+CD122+Tregs and M2-like macrophages in mice	Zhang et al[79], 2020

CCR: C-C chemokine receptor; HGF: Hepatocyte growth factor; HGFR: Hepatocyte growth factor receptor; HCC: Hepatocellular carcinoma; PD-1: Programmed cell death protein 1; miR: micro ribonucleic acid; IL: Interleukin; GDF: Growth differentiation factor; Treg: Regulatory T cells; Th: T helper; IFN: Interferon; VEGFR: Vascular endothelial growth factor receptor; CTLA: Cytotoxic T lymphocyte-associated antigen; TGF-β: Transforming growth factor-beta.

Table 2 Clinical trials by targeting regulatory T cells to modulate the immune response

Trial	Phase	Treatment	Results	Ref.
NCT02476123	I	Anti-CCR4 antibody mogamulizumab	Treg depletion induced by anti-CCR4 antibody (mogamulizumab), in combination with anti-PD-1 antibody (nivolumab) showed antitumor activity and increased CD8+ T cell infiltration	Doi et al[78], 2019; Sánchez-Fueyo et al[83], 2020
NCT02166177	I	Intravenous infusion of ex vivo expanded Tregs	Treg transfer can transiently increase circulating Tregs and inhibit anti-donor T cell responses in patients with liver transplants	Fueyo et al[83], 2020
NCT02166177	I	Autologous Treg therapy	To defect safety and efficacy study of regulatory T cell therapy in liver transplant patients	Whitehouse et al[84], 2017
NCT01624077	I	Injection of Tregs	To defect safety and efficacy study of regulatory T cell therapy in liver transplant patients	Whitehouse et al[84], 2017
NCT03654040	I	A single dose of alloantigen-reactive Tregs (arTreg) (≥ 90 × 106 total cells)	It is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients	Cvetkovski et al[85], 2021
NCT03577431		arTreg-CSB (2.5 × 106 cells)
NCT02260375	I	Infusion of mesenchymal stromal cells	MSC infusion in liver transplant recipients slightly increased circulating Treg/memory Treg over baseline, without a statistically significant, but not in the control group	Casiraghi et al[86], 2021
NCT02027116	I	DNA vaccine GLS-6150	GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effects	Han et al[87], 2020
NCT02174276	II	GS-4774, a yeast-based therapeutic vaccine	Treatment with GS-4774 increased T-cell functions by increasing the production of IFN-γ and TNF and reducing the cell number of Tregs	Boni et al[88], 2019
NCT02360592	IV	Combined therapy with interferon plus IL-1 and hepatitis B Vaccine	Combination therapy increased the level of hepatitis B surface antigen with partial restoration of Tregs and NK cells	Wu et al[89], 2019
NCT02072486	None	Sorafenib, a multiple kinase inhibitor	Treatment with sorafenib can significantly suppress extracellular signal-regulated kinases+ FMS-like tyrosine kinase 3+ Tregs and myeloid-derived suppressor cells to benefit the survival of HCC patients	Kalathil et al[90], 2019

CCR: C-C chemokine receptor; CSB: Co-stimulatory blockade; PD-1: Programmed cell death protein 1; Treg: Regulatory T cells; MSC: Mesenchymal stromal cells; DNA: Deoxyribonucleic acid; GLS: Glutaminase; IFN: Interferon; TNF: Tumor necrosis factor; IL: Interleukin; NK: Natural killer; FMS: Feline McDonough sarcoma.