FRI-132
In vitro modulation by TLR8 agonist GS-9688 of multiple
regulatory cell types in patients with chronic hepatitis B
Oliver E Amin1, Emily Colbeck1, Stephane Daffis2,
Divya Pattabiraman2, Colette Sitali3, William Rosenberg4,
Simon Fletcher2, Mala Maini1, Laura J Pallett1. 1UCL, Infection and
Immunity, London, United Kingdom; 2Gilead Sciences, Foster City,
United States; 3UCL, Infection, Immunity and Transplantation, London,
United Kingdom; 4UCL, Infection, Immunity and Transplantation,
London, United Kingdom
Email: [email protected]
Background and aims: HBV-specific T cell responses are characterised
by functional exhaustion and premature deletion.
Immunosuppressive cell types targeting this antiviral T cell response
include granulocytic myeloid-derived suppressor cells (gMDSC),
CD4 + regulatory T cells (Tregs), and regulatory TRAIL + NK cells.
Signalling through different toll-like receptors (TLR) induces selective
cytokine profiles capable of differentially modulating immune cell
subsets. Herewe have tested the impact of a selective small molecule
agonist of TLR8 (GS-9688), currently in Phase 2 trials for the
treatment of chronic HBV infection (CHB), on these three different
regulatory populations and on HBV-specific CD8 + T cells in vitro.
Method: PBMC obtained from a cohort of CHB patients were treated
with 1-500 nM GS-9688 for 2-7 days. Cytokine responses were
measured by luminex assay. Sixteen-colour flowcytometry was used
to analyse changes in the frequency and phenotype of gMDSC
(CD11bhighCD33+HLADR-CD14-CD15+, n = 14 CHB patients), Tregs
(CD4+CD25hiCD127loFoxp3+, n = 8 CHB patients), NK cells (CD3-
CD56+, n = 20 CHB patients) and HBV-specific CD8+ T cells (binding a
panel of HLA-A2/peptide dextramers, n = 12 CHB patients).
Results: In line with previous studies, GS-9688 induced cytokines in
PBMC cultures (e.g. TNF-α, IFN-γ, IL-12p70 and IL-18) with the
potential to modify regulatory cell subsets. Consistent with this
cytokine profile, GS-9688 treatment induced gMDSC to switch to a
more mature and less suppressive phenotype, resulting in a > 50%
reduction in the frequency of this regulatory cell type (p < 0.001).
Similarly, GS-9688 treatment induced a dose-dependent reduction in
the frequency of conventional Tregs (p < 0.05). In contrast, GS-9688
triggered dose-dependent activation of CD56bright and CD56dim NK
cells, and a rapid upregulation of their expression of the death ligand
TRAIL (p < 0.05). Despite this, HBV-specific CD8+ T cell frequencies
remained stable, suggesting they were protected from NK cell TRAILmediated
deletion in the presence of GS-9688.
Conclusion: Overall, these in vitro data suggest that GS-9688 has the
potential to reduce the suppressive activity of regulatory populations
in the liver that collectively limit the antiviral response of HBVspecific
T cells. Further studies will explore how HBV-specific T cells
are protected from deletion by the GS-9688-driven expansion of
TRAIL+ NK cells and whether these changes are recapitulated using
intrahepatic lymphocytes. 作者: newchinabok 时间: 2019-4-8 15:59