Restoration of HBV-specific CD8 + T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy
Dongyao Wang # 1 2 , Binqing Fu # 1 2 , Xiaokun Shen 1 2 , Chuang Guo 1 2 , Yanyan Liu 3 , Junfei Zhang 3 , Rui Sun 1 2 , Ying Ye 3 , Jiabin Li 4 , Zhigang Tian 5 6 , Haiming Wei 7 8
Affiliations
Affiliations
1
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China.
2
Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China.
3
Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China.
4
Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China. [email protected].
5
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
6
Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
7
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
8
Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China. [email protected].
#
Contributed equally.
PMID: 34737296 DOI: 10.1038/s41392-021-00776-0
Abstract
Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.