Copyright ©The Author(s) 2022.
World J Gastroenterol. Jul 21, 2022; 28(27): 3346-3358
Published online Jul 21, 2022. doi: 10.3748/wjg.v28.i27.3346
Table 1 Treatment options for hepatocellular carcinoma by targeting regulatory T cells and relative signaling pathways
CCR4 antagonistCCR4Administration 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 sorafenibGao et al[37], 2022
miR-26aIL6/Stat3 and HGF/c-MetThe 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, respectivelyYang et al[65], 2013; Yang et al[66], 2014
GDF15 neutralizing antibodyGDF15/CD48Inhibiting GDF15 function by a neutralizing antibody can effectively eradicate HCC and promote a tumoricidal immune response in miceWang et al[53], 2021
Supplementation of Lactobacillus rhamnosus GG or its culture supernatantThe ratio of Treg and Th17 cellsSupplementation 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 injuryChen et al[22], 2016; Wang et al[72], 2013; Wang et al[73], 2012
Prohep, a novel probiotic mixtureGut microbiota and Treg differentiationProbiotic 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 OscillibacterLi et al[74], 2016
Anti-PD-1 and anti-PD-L1 antibodiesPD-1 and PD-L1Another 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 HCCLanghans et al[76], 2019
Dual anti-PD-1/VEGFR-2 therapyVEGFR-2 and PD-1Dual 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 tissueShigeta et al[75], 2020
Anti-CTLA-4 monoclonal antibodyTregsTreg 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 treatmentLee et al[77], 2020
ResveratrolTregs and immunosuppressive cytokines including TGF-β1 and IL-10Treatment 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 miceZhang et al[79], 2020
Table 2 Clinical trials by targeting regulatory T cells to modulate the immune response
NCT02476123IAnti-CCR4 antibody mogamulizumabTreg depletion induced by anti-CCR4 antibody (mogamulizumab), in combination with anti-PD-1 antibody (nivolumab) showed antitumor activity and increased CD8+ T cell infiltrationDoi et al[78], 2019; Sánchez-Fueyo et al[83], 2020
NCT02166177IIntravenous infusion of ex vivo expanded TregsTreg transfer can transiently increase circulating Tregs and inhibit anti-donor T cell responses in patients with liver transplantsFueyo et al[83], 2020
NCT02166177IAutologous Treg therapyTo defect safety and efficacy study of regulatory T cell therapy in liver transplant patientsWhitehouse et al[84], 2017
NCT01624077IInjection of TregsTo defect safety and efficacy study of regulatory T cell therapy in liver transplant patientsWhitehouse et al[84], 2017
NCT03654040IA 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 recipientsCvetkovski et al[85], 2021
NCT03577431arTreg-CSB (2.5 × 106 cells)
NCT02260375IInfusion of mesenchymal stromal cellsMSC infusion in liver transplant recipients slightly increased circulating Treg/memory Treg over baseline, without a statistically significant, but not in the control groupCasiraghi et al[86], 2021
NCT02027116IDNA vaccine GLS-6150GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effectsHan et al[87], 2020
NCT02174276IIGS-4774, a yeast-based therapeutic vaccineTreatment with GS-4774 increased T-cell functions by increasing the production of IFN-γ and TNF and reducing the cell number of TregsBoni et al[88], 2019
NCT02360592IVCombined therapy with interferon plus IL-1 and hepatitis B VaccineCombination therapy increased the level of hepatitis B surface antigen with partial restoration of Tregs and NK cellsWu et al[89], 2019
NCT02072486NoneSorafenib, a multiple kinase inhibitorTreatment 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 patientsKalathil et al[90], 2019