JoséMaríaRojo, Pilar Portolés
114
(122). A B7 family receptor expressed bymelanoma 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 isnot surprising, then, that antibodiesblockingCTLA-‐4or thePD-‐1/PD1
ligands are currently used in anti-‐cancer therapy, supposedly to unleash
suppressedanti-‐tumor immunity(128).
Since p110
α
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 p110
α
, 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 p110
α
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
p110
δ
-‐ or p110
γ
-‐specific inhibitors would be of no interest to cancer therapy,
except in hematologic malignancies were the levels of these subunits is naturally
high. Interestingly, p110
δ
participates inantigen, cytokineandchemokinereceptor
signaling in B lymphocytes, and indeed one p110
δ
inhibitor CAL-‐101 has been
used in the treatment of some relapsedor refractoryB-‐cellmalignancies 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
inhibitionof signalsdeliveredby the tumorenvironment that sustain leukemiaand
lymphomacells.
It is yet more surprising the data showing that p110
δ
inhibitors can be
useful in the treatment of solid tumors that do not harbor p110
δ
mutations.
Tzenaki et al. have reported that breast andprostate cancer cells canpossess high
levels of p110δ 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)P
3
levels (48,49). Thus, p110δ-‐selective PI3K
inhibitors might be useful in certain solid tumor therapy by directly inhibiting
p110δ signaling as well as by indirectly activate PTEN to diminish general
PtdIns(3,4,5)P
3
levels. At the same time, the use of p110
δ
inhibitors in these cases
doeshave a truedanger for suppressinganti-‐tumor immune responses, but also to
responsesagainstpathogens.
