Page 116 - 80_01

José
María
Rojo,
Pilar
Portolés

(122).
A
B7
family
receptor
expressed
by
melanoma
and
other
tumor
cells
is
the

ICOS
ligand
that
can
directly
induce
the
activation
and
expansion
of
ICOS-­-
expressing
Treg
cells
within
the
tumor,
suppressing
anti-­-tumor
rejection,
or

alternatively
induce
the
recruitment
to
the
tumor
of
ICOS-­-ligand-­-expressing

dendritic
cells
that
favor
Treg
function
(123-­-127).
Another
inhibitory
CD28-­-like

molecule
expressed
by
Treg
cells
is
CTLA-­-4
(Cytotoxic
T-­-Lymphocyte
Antigen
4,

CD152).
It
is
not
surprising,
then,
that
antibodies
blocking
CTLA-­-4
or
the
PD-­-1/PD1

ligands
are
currently
used
in
anti-­-cancer
therapy,
supposedly
to
unleash

suppressed
anti-­-tumor
immunity
(128).

Since
p110a
are
frequently
mutated
in
cancer,
PI3K
inhibitors
directed
at

this
isoform,
alone
or
together
with
other
kinases,
are
currently
being
tested
in

antitumour
therapies
(51).
Although
in
our
experience
inhibition
of
p110a,
alone

or
together
with
DNA-­-PK
can
have
a
significant
impact
in
immune
responses
and

lymphocyte
viability
(82,117),
other
data
suggest
minimal
damage
of
p110a

inhibition
to
immune
reactions
and
likely
to
anti-­-tumor
immunity
(81).
Thus,
it

might
seem
that
only
broad
PI3K
inhibitors,
or
Akt
and
mTOR
inhibitors,
might

have
a
significant
impact
on
anti-­-tumor
responses,
whereas
immunosuppressive

p110d-­-
or
p110?-­-specific
inhibitors
would
be
of
no
interest
to
cancer
therapy,

except
in
hematologic
malignancies
were
the
levels
of
these
subunits
is
naturally

high.
Interestingly,
p110d
participates
in
antigen,
cytokine
and
chemokine
receptor

signaling
in
B
lymphocytes,
and
indeed
one
p110d
inhibitor
CAL-­-101
has
been

used
in
the
treatment
of
some
relapsed
or
refractory
B-­-cell
malignancies
including

chronic
lymphocitic
leukemia
(CLL),
non-­-Hodgkin’s
lymphoma
(NHL),
acute

myeloid
leukemia
(AML),
and
multiple
myeloma
(MM),
with
clear
clinical

responses
in
CLL
and
some
NHL
(49,129).
Surprisingly,
this
is
due
in
part
to

inhibition
of
signals
delivered
by
the
tumor
environment
that
sustain
leukemia
and

lymphoma
cells.

It
is
yet
more
surprising
the
data
showing
that
p110d
inhibitors
can
be

useful
in
the
treatment
of
solid
tumors
that
do
not
harbor
p110d
mutations.

Tzenaki
et
al.
have
reported
that
breast
and
prostate
cancer
cells
can
possess
high

levels
of
p110d
that
not
only
enhance
cellular
PI3K
activity
but
also
indirectly

inhibit
the
tumor
suppressor
phosphatase
PTEN
via
RhoA
and
ROCK
activation,

further
enhancing
PtdIns(3,4,5)P3
levels
(48,49).
Thus,
p110d-­-selective
PI3K

inhibitors
might
be
useful
in
certain
solid
tumor
therapy
by
directly
inhibiting

p110d
signaling
as
well
as
by
indirectly
activate
PTEN
to
diminish
general

PtdIns(3,4,5)P3
levels.
At
the
same
time,
the
use
of
p110d
inhibitors
in
these
cases

does
have
a
true
danger
for
suppressing
anti-­-tumor
immune
responses,
but
also
to

responses
against
pathogens.

114