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Class
I
phosphoinositide
3-­-kinases
in
immunity…

Intriguingly,
we
have
later
found
that
other,
more
specific
p110a
inhibitors
like

A66
do
not
have
a
similar
effect
on
lymphocyte
apoptosis
(82),
and
it
is
probably

the
sum
of
p110a
and
DNA-­-PK
inhibition
that
produced
the
effect
on
cell
viability

(unpublished
data).

12.d.
Experimental
colitis
and
psoriasis.

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,
and
NF-­-?B
transcription
in

lymphoid
or
monocyte
cells
or
cell
lines,
secretion
of
the
inflammatory
cytokines

IL-­-6
and
TNF-­-a
by
activated
monocytes,
or
reduced
the
expression
of
adhesion

molecules
by
TNF-­-a
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
110dD910A
cannot
prevent
the

development
of
the
disease,
suggesting
the
importance
of
the
p110d
isoform
to
the

effector
function
of
Treg
cells
(96)

Last,
PI3K
have
a
role
in
the
psoriasis-­-like
dermatitis
induced
by
imiquimod

(IMQ).
In
this
model,
the
T
lymphocytes
of
the
?d
TCR
subset
produce
IL-­-17

essential
to
the
clinical
symptoms
of
the
disease.
After
establishing
that
mice

transgenic
for
the
110dD910A
inactive
mutant
or
p110?-­-/-­-
knockouts
are
not

susceptible
to
dermatitis
and
have
diminished
production
of
IL-­-17A
and
F
(119),

Roller
et
al.
went
on
to
show
that
the
p110d
inhibitor
IC87114
or
p110?
inhibitors

like
AS605240
inhibited
IL-­-17
and
IFN-­-?
production
by
activated
peripheral
blood

lymphocytes
from
psoriatic
and
healthy
donors,
or
IFN-­-?
production
by
activated

blood
TCR?d
T
lymphocytes
(119).

13.
PI3K
AND
CANCER:
IMPACT
OF
PI3K
INHIBITORS
ON
CANCER
CELLS
AND

ANTI-­-CANCER
IMMUNITY:
A
DOUBLE-­-EDGED
SWORD?

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
immune
mechanisms
developed
by
the
host
(immunoediting)

(120,121).
CD8
T
lymphocytes
and
IFN-­-?
seem
to
be
major
cellular
and
molecular

mediators
of
anti-­-cancer
responses.
One
mechanism
used
by
tumor
cells
to
evade

immune-­-mediated
rejection
is
by
expressing
inhibitory
B7
family
molecules
like

B7-­-H1
and
B7-­-H4
that
bind
the
inhibitory
CD28
family
ligand
programmed
death-­-1

(PD-­-1)
expressed
on
the
surface
of
activated
T
cells,
B
cells
and
macrophages

113