Class I phosphoinositide3-‐kinases in immunity…
113
Intriguingly, we have later found that other, more specific p110
α
inhibitors like
A66 do not have a similar effect on lymphocyte apoptosis (82), and it is probably
the sumof p110
α
andDNA-‐PK inhibition that produced the effect on cell viability
(unpublisheddata).
12.d. Experimental colitisandpsoriasis.
Oral treatment with PIK-‐75 was previously shown to inhibit another
experimental inflammation, namely colitis induced by oral administration of
dextran-‐sulfate, a model for human inflammatory bowel disease (118).
In vitro
,
PIK-‐75 inhibited AKT phosphorylation, IKK activation, andNF-‐
κ
B transcription in
lymphoid or monocyte cells or cell lines, secretion of the inflammatory cytokines
IL-‐6 and TNF-‐
α
by activated monocytes, or reduced the expression of adhesion
molecules by TNF-‐
α
in endothelial cells (118). As mentioned before, functional
CD4
+
Treg cells are essential to prevent the development of experimental colitis,
and mice expressing the kinase-‐dead mutant 110δ
D910A
cannot prevent the
development of thedisease, suggesting the importanceof thep110
δ
isoformto the
effector functionofTregcells (96)
Last, PI3Khavea role in thepsoriasis-‐likedermatitis inducedby imiquimod
(IMQ). In this model, the T lymphocytes of the
γδ
TCR subset produce IL-‐17
essential to the clinical symptoms of the disease. After establishing that mice
transgenic for the 110δ
D910A
inactive mutant or p110
γ
-‐/-‐
knockouts are not
susceptible to dermatitis and have diminished production of IL-‐17A and F (119),
Roller et al. went on to showthat thep110
δ
inhibitor IC87114or p110
γ
inhibitors
likeAS605240 inhibited IL-‐17 and IFN-‐
γ
productionby activatedperipheral blood
lymphocytes frompsoriatic and healthy donors, or IFN-‐
γ
production by activated
bloodTCRγδT lymphocytes (119).
13. PI3K AND CANCER: IMPACT OF PI3K INHIBITORS ON CANCER CELLS AND
ANTI-‐CANCER IMMUNITY: ADOUBLE-‐EDGEDSWORD?
Tumor cells can express tumor antigens of various kinds that can elicit
efficient immunity as an extrinsic mechanism to control and suppress cancer
growth (immunosurveillance), establishing a dynamic equilibrium or even
complete rejection of tumor cells. However, tumor specific responses can also
promote tumor growth through the selection of rare mutant tumor cells able of
oppose or evade the immunemechanisms developedby thehost (immunoediting)
(120,121). CD8 T lymphocytes and IFN-‐
γ
seemto bemajor cellular andmolecular
mediators of anti-‐cancer responses. Onemechanismused by tumor cells to evade
immune-‐mediated rejection is by expressing inhibitory B7 family molecules like
B7-‐H1andB7-‐H4 that bind the inhibitoryCD28 family ligandprogrammeddeath-‐1
(PD-‐1) expressed on the surface of activated T cells, B cells and macrophages
