Ribavirin and IFN-α combination therapy induces CD4+ T-cell proliferation and Th1 cytokine secretion in patients with chronic hepatitis B

Background/Aims: Minimal residual leukemia cells (MRLs) are difficult to eradicate through traditional treatment and therefore remain to be a major threat to the long-term survival of leukemia patients. Tumor-derived exosomes (TEXs), which carry tumor associated antigens (TAA), may be a potential cell-free tumor vaccine for the specific eradication of MRLs. However, TEXs are intended to be less immunogenic due to exosomal TGF-β1. To further optimize the efficacy of TEX-based vaccines, we investigated whether exosomes from TGF-β1 silenced leukemia cells (LEXTGF-β1si) had an increased potential to induce a specific antitumor effect compared with non-modified exosomes. Methods: Exosomal TGF-β1 was downregulated via lentiviral shRNA silencing of TGF-β1 in leukemia cells. The characteristics of LEXTGF-β1si were determined via electron microscopy, western blot analysis, and flow cytometry. The antitumor effect of LEXTGF-β1si was evaluated by detecting the properties of LEXTGF-β1si-pulsed dendritic cells (DCs), CD4+ T-cell proliferation, Th1 cytokine secretion, specific CTL activity, and NK cell function. Moreover, to verify the superiority of LEXTGF-β1si immunization, LEXTGF-β1si was subcutaneously injected into DBA/2 mice: either followed by tumor challenge or tumor bearing. Results: The lentiviral shRNA silencing of TGF-β1 in parental leukemia cells successfully downregulated the TGF-β1 level in leukemia cell derived exosomes (LEX). LEXTGF-β1si was uptaken by DCs and was more potent in promoting DC function by upregulating the surface expression of costimulatory factors and MHC class II molecules, while inducing the secretion of IL-12p70 and TNF-α. Furthermore, immunization with LEXTGF-β1si facilitated CD4+ T-cell proliferation and Th1 cytokine secretion, and stimulated stronger specific cytotoxic lymphocyte (CTL) response and nature killer (NK) cell cytotoxicity more efficiently compared to non-modified LEX. In mice models, immunization with LEXTGF-β1si resulted in a more potent capability to inhibit tumor growth and to prolong survival, suggesting that LEXTGF-β1si was more effective in both protective and therapeutic antitumor tests than non-modified LEX. Conclusions: These data suggested that down-regulation of exosomal TGF-β1 effectively induced potent anti-tumor immunity. Our strategy of optimizing exosome vaccine may have promising potential for leukemia immunotherapy.

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IFN-α Suppresses Myeloid Cytokine Production, Impairing IL-12 Production and the Ability to Support T-Cell Proliferation

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa064 ◽

2020 ◽

Vol 222 (1) ◽

pp. 148-157

Author(s):

Aman Mehrotra ◽

June Ann D’Angelo ◽

Amanda Romney-Vanterpool ◽

Tom Chu ◽

Antonio Bertoletti ◽

...

Keyword(s):

Cell Proliferation ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Cytokine Production ◽

Antigen Presenting Cells ◽

T Cell Proliferation ◽

Hla Dr ◽

Antigen Presenting

Abstract Background Interferon-α (IFN-α) can suppress production of T-cell polarizing cytokines or induce inhibitory antigen-presenting cells that suppress T-cell activation. Previous studies showed that IFN-α therapy fails to boost virus-specific T-cell immunity in patients with chronic hepatitis B virus infection. Our aim was to determine whether IFN-α exposure alters human antigen-presenting cell function in vivo. Methods We investigated the immunomodulatory effects using peripheral blood mononuclear cells from healthy donors exposed to IFN-α and chronic hepatitis B (CHB) patients starting IFN-α therapy. Results IFN-α increased HLA-DR, CD80, CD86, and PD-L1 expression on healthy donor monocytes. In contrast to the activated phenotype, IFN-α inhibited Toll-like receptor-induced cytokine production and monocyte-induced T-cell proliferation. In CHB patients, peg-IFN treatment induced an interferon-stimulated gene signature in monocytes and increased HLA-DR, CD80, CD86, and PD-L1 expression. As early as 3 days after CHB patients started treatment, IFN-α inhibited monocyte cytokine production and T-cell stimulation ex vivo. IFN-α-mediated inhibition of IL-12 production, rather than inhibitory receptor expression, was responsible for inhibition of T-cell proliferation. Addition of IL-12 restored T-cell proliferation to baseline levels. Conclusions Understanding how professional antigen-presenting cells respond to immunomodulation is important for both new innate and adaptive-targeted immunotherapies. Clinical Trials Registration NCT00962871.

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