NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

Abstract

A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.

Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location

“…Based on the aforementioned results, we hypothesized that enhanced CD56 bright NK cell activation and function in left-side CRC might also be beneficial for prolonged patient survival. Therefore, we performed additional analysis to examine whether the 4-1BB and interferon-α signaling pathways, which are known to reinforce the function of NK cells ( 34 , 35 ), could also prolong OS for left-side CRCs. As expected, we observed significantly increased survival in patients with more active 4-1BB and interferon-α signaling pathways in left-side CRCs (Figure 3 C; 4-1BB: p = 0.00427, IFNA: p = 0.0187 for left side and 4-1BB: p = 0.961, IFNA: p = 0.549 for right side).…”

Kushenin combined with adefovir dipivoxil affects the HBV-DNA load in serum, immune functions and liver functions of patients with chronic hepatitis B

“…In Traditional Chinese Medicine, hepatic cirrhosis after hepatitis B is also included in the range of ‘dilation’ and ‘coagulation’ ( 11 ), and it is believed that it is caused by deficiency in origin and excess in superficiality, which are intermingled with the disorder of liver and spleen. These lead to the stagnation of qi in liver and dysfunction of spleen in transport, and further contribute to the blockage in transport of moisture and accumulation of moisture and turbidity ( 12 ). In addition, the accumulated moisture affects the activities of qi , and thus cause imbalance in the transport controlled by spleen, deficiency of yang-qi and significant increase in turbid yin .…”

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics

“…In a recent study, patients treated with IFN; NKp30+ NK cells were found to be associated with HBV control, with IL‐15 contributing to the upregulation of functional antiviral NK cells. Interestingly, in nonresponders to IFN, NKp30+ NK cells were found to be dysfunctional with an expansion of the inhibitory receptor NKG2A . In the same cohort of patients, an expansion of CD3 bright CD56+ T cells (innate‐like T cells) expressing high levels of NKG2A and low CD8 was associated with nonresponse to IFN.…”

“…Interestingly, in nonresponders to IFN, NKp30+ NK cells were found to be dysfunctional with an expansion of the inhibitory receptor NKG2A. 48 In the same cohort of patients, an expansion of CD3 bright CD56+ T cells (innate-like T cells) expressing high levels of NKG2A and low CD8 was associated with nonresponse to IFN. These nonresponders had increased levels of TIM3+ CD3 bright CD56+ T cells, which negatively correlated with IFNγ production contributing to the dysfunction of these cells and potentially contributing to poor responses to IFN.…”