Hepatocellular carcinoma in viral and autoimmune liver diseases: Role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment

Table 1 Regulatory T cell function and recruitment in hepatocellular carcinoma

Treg function in HCC		Ref.
Molecule	Target
IL-10	IL-10R	Marra and Tacke[90]
IL-35	IL-12Rβ2	Shen et al[91]
TGF-β	TGF-βR	Fu et al[92]
CTLA-4	CD80/CD86	Chen et al[93]
CD39-CD73	ATP	Chen et al[94]
IL-2 Rα (CD 25)	IL-2	Li et al[95]
LAG3	MHC class IImolecules	Cabrera et al[96]
Treg recruitment in HCC		Ref.
Molecule	Receptor
CCL22	CCR4	Li et al[97]
CCL5	CCR5	Cheng et al[98]
CCL28	CCR3, CCR10	Singh et al[99]

CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; LAG3: Lymphocyte activation gene 3 protein; IL: Interleukin; TGF-β: Transforming growth factor β; Treg: Regulatory T cell; HCC: Hepatocellular carcinoma.

Table 2 Clinical trials assessing immune cell populations as study outcome

Clinical trials identifier	Official title	Phase	Secondary outcome	Intervention/treatment	Status
NCT04518774	The safety assessment of ex vivo expanded allogeneic γδT cells in hepatocellular carcinoma patients in phase 1 clinical trial	I	Number and phenotype of γδT cells in peripheral blood	Patients will receive 3 cycles of ex vivo expanded allogeneic γδT cells treatments, at four-weeks' intervals, each cycle has 2 infusions. Ex vivo expanded γδT cells are transfused to patients in a dosage escalated manner (dose escalation, 1 × 107, 3 × 107, 9 × 107 per kg of body weight)	Recruiting
NCT03841201	IMMUNIB: An open-label, single-arm phase II study of immunotherapy with nivolumab in combination with lenvatinib for advanced stage	II	Immune cell infiltrates FOXP3 expression	Lenvatinib peroral qd (8 mg for patients with body weight < 60 kg and 12 mg for patients with body weight ≥ 60 kg); Nivolumab i.v. q2w (240 mg fixed dose IV) max. 36 cycles	Recruiting
NCT04777708	Pilot feasibility study of intratumoral BO-112 in combination with pembrolizumab for advanced hepatocellular carcinoma	I	Intratumoral CD4+, CD8+ expression and cluster of differentiation 56 (CD56+) expression (natural killer cells)	Patients receive pembrolizumab IV over 30 min on day 1 of odd number cycles. Patients also receive BO-112 by intratumoral injection on day 1, 8, and 15 of cycle 1, and day 15 of subsequent cycles. Treatment repeats every 3 wk for up to 17 cycles in the absence of disease progression or unacceptable toxicity	Not yet recruiting
NCT04721132	An open-label, phase II, pre-operative study of atezolizumab plus bevacizumab for resectable hepatocellular carcinoma	II	To measure baseline and longitudinal changes of immune infiltration including CD8/regulatory T cell ratio and CD68+ density, and fibrosis stage	Patients receive atezolizumab IV over 30-60 min and bevacizumab IV over 30-90 min on day 1. Treatment repeats every 21 d for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery during week 12	Recruiting
NCT00396682	Elimination of CD4+CD25+ regulatory T cells in patients with advanced hepatocellular carcinoma after treatment with cyclophosphamide	I	Function and Phenotype of CD4+CD25+ regulatory T cells	Cyclophosphamide 150 mg to 250 mg to 350 mg	Completed

Clinical trials assessing as secondary study outcomes different immune cell populations, including CD4+CD25+ Tregs (https://www.clinicaltrials.gov/).