An immune modulatory role for the fes proto-oncogene
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Date
2015-07-21
Authors
Alotaibi, Faizah
Keyword
fes oncogene , immune system
Abstract
The Fes protein tyrosine kinase is abundantly expressed in phagocytic immune cells, including
tumor associated macrophages. Fes knockout mice (fes-/-) display enhanced sensitivity to LPS,
and this was shown to be associated with increased NF-κB signaling and TNFα production from
fes-/- macrophages. Interestingly, tumor onset in the mouse mammary tumor virus (MMTV-Neu)
transgenic mouse model of breast cancer is significantly delayed in fes-/- mice, and this was
associated with increased frequency of CD11b+ myeloid and CD3+ T cells in the premalignant
mammary glands. Recent studies have also implicated Fes in cross-talk between MHC-I and the
NF-κB and IRF-3 pathways in macrophages. Signal 3, the production of inflammatory cytokines
and Type I interferons downstream of NF-κB and IRF-3 pathways in antigen presenting cells, is
considered an important component of T-cell activation, after engagement of T cell receptor by
MHC presented antigen (Signal 1) and co-receptors by their ligands (Signal 2).
Using a lymphocytic choriomeningitis virus (LCMV) model of immune activation, I
show that LPS stimulated fes-/- macrophages promote more robust activation of LCMV antigenspecific
CD8+ T cells than wild type macrophages (fes+/+). Furthermore, LPS stimulated fes-/-
macrophages showed increased phosphorylation of NF-B and IRF-3. I also showed that Fes colocalizes
with MHC-I in dynamic vesicular structures within macrophages. These observations
are consistent with a model where Fes regulates Signal 3 in antigen presenting cells through roles
in cross-talk between MHC-I and the NF-kB and IRF-3 signaling pathways. This suggests that
Fes plays an immune checkpoint role at the level of Signal 3, and that Fes inhibition could
promote tumor immunity through increased Signal 3 driven T cell activation.