New TLR7 agonists with improved humoral and cellular immune responses

Katherine C Upchurch; José R Boquín; Wenjie Yin; Yaming Xue; HyeMee Joo; Robert R Kane; SangKon Oh

doi:10.1016/j.imlet.2015.09.007

New TLR7 agonists with improved humoral and cellular immune responses

Immunol Lett. 2015 Nov;168(1):89-97. doi: 10.1016/j.imlet.2015.09.007. Epub 2015 Sep 14.

Authors

Katherine C Upchurch¹, José R Boquín², Wenjie Yin¹, Yaming Xue³, HyeMee Joo¹, Robert R Kane⁴, SangKon Oh⁵

Affiliations

¹ Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA.
² Baylor University, Department of Chemistry and Biochemistry, One Bear Place #97348, Waco, TX 76798, USA.
³ Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA.
⁴ Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA; Baylor University, Department of Chemistry and Biochemistry, One Bear Place #97348, Waco, TX 76798, USA.
⁵ Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA. Electronic address: [email protected].

PMID: 26381186
DOI: 10.1016/j.imlet.2015.09.007

Abstract

Toll-like receptor 7 (TLR7) agonists are of interest as vaccine adjuvants and cancer therapeutics. Therefore, development of new TLR7 agonists that can efficiently promote host immune responses without evoking side effects is of great importance. Here, we describe two new compounds, J4 and F4, which elicit intracellular signaling exclusively via TLR7. Interestingly, both J4 and F4 induced less cytokine secretion (IL-1β, IL-6, IL-10, IL-12p40, TNFα, and IL-12p70) from myeloid dendritic cells (mDCs) and monocytes than CL075 and R848; however, they all generated similar levels of phenotype maturation of antigen presenting cells (APCs), including plasmacytoid DCs. We further found that J4- and F4-induced APC activation was largely dependent on the activation of NF-κB and p38. Lastly, J4 and F4 could efficiently promote B cell proliferation and plasmablast differentiation as well as antigen-specific CD8(+) T cell responses in human in vitro. Therefore, these new TLR7 agonists could be employed to facilitate the development of new therapeutics and vaccine adjuvants against cancers and microbial infections.

Keywords: Adjuvant; Dendritic Cell; TLR7; Vaccine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemistry
Adenosine / pharmacology
Adjuvants, Immunologic / chemistry
Adjuvants, Immunologic / pharmacology*
Antigen-Presenting Cells / drug effects
Antigen-Presenting Cells / immunology
Antigen-Presenting Cells / metabolism
B-Lymphocytes / drug effects
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cell Differentiation / drug effects
Cell Differentiation / immunology
Cell Proliferation / drug effects
Cells, Cultured
Cytokines / immunology
Cytokines / metabolism
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / metabolism
Flow Cytometry
HEK293 Cells
Humans
Immunity, Cellular / drug effects*
Immunity, Cellular / immunology
Immunity, Humoral / drug effects*
Immunity, Humoral / immunology
Inflammation Mediators / immunology
Inflammation Mediators / metabolism
Molecular Structure
Monocytes / drug effects
Monocytes / immunology
Monocytes / metabolism
NF-kappa B / immunology
NF-kappa B / metabolism
Toll-Like Receptor 7 / agonists*
Toll-Like Receptor 7 / genetics
Toll-Like Receptor 7 / metabolism

Substances

Adjuvants, Immunologic
Cytokines
Inflammation Mediators
NF-kappa B
TLR7 protein, human
Toll-Like Receptor 7
Adenosine