Table Of ContentOncoImmunology1:2,224–226;March/April2012;G2012LandesBioscience
FIST, a sword and shield fusokine for cancer
immunotherapy
Claudia Penafuerte1 and Jacques Galipeau2,*
1TheRosalind&MorrisGoodmanCancerResearchCentre;McGillUniversity;Montreal,QCCanada;2EmoryUniversityWinshipCancerInstitute;DepartmentofHematologyand
MedicalOncologyandDepartmentofPediatrics;Atlanta,GAUSA
Keywords: IL-2, TGFβ Receptor II
To antagonize tumor-derived TGFb contemporaneously to anticancer immunotherapy, we genetically engineered a
fusionproteincouplingIL-2andtheectodomainofTGFbreceptorII(FusionofInterleukin-2andSolubleTGFbreceptor–
a.k.a.FIST).FISTpossessesintriguinggain-of-functionpropertiesandinducespotentactivationofIL2-receptorexpressing
cells and inhibits tumor-derived angiogenesis. Thus FIST constitutes a first-in-class biological that couples anti-
angiogenesis toan immuneantitumor response.
© 2012 Landes Bioscience.
TGFb Role in Tumor Progression SMAD3 and SMAD4. TGFβ act as a The question then arises: among the
prometastatic and proangiogenic factor myriadpro-inflammatorycytokinesknown
The balance between proliferative and in late stage cancer by constitutively to date, which would be best combined
inhibitory signals is essential to maintain inducing epithelial to mesenchymal to a TGFβ decoy to achieve enhanced
immune homeostasis. In late stage tumor transition (EMT) and tumor associated anti-cancer immunity?
progression, immunostimulatory signals angiogenesis.1 The strategy of blocking
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provide by proinflammatory cytokines are tumor-derived active TGF for therapeutic IL-2 as Partner Cytokine for sTbRII
antagonized by tumor derived immuno- proposes has been extensively explored.
suppressive cytokines, such as TGFβ. The Several therapeutic approaches target Proinflammatory cytokines such as IL-2
members of the Transforming Growth TGFβ pathway for the treatment of a constitute useful adjuvants for which
Factor β (TGFβ) family are cytokines number of invasive cancer such as breast extensive clinical experience exists for the
involved in essential cellular functions cancerandmelanoma.Intracellularinhibi- treatment of cancer. IL-2 is well-known
suchasproliferation,differentiation,apop- tion of TGFβ receptor I (TβRI) kinase factorforlymphocyteactivationandclonal
tosis, tissue remodeling, angiogenesis, with a small-molecule inhibitors, effec- expansion. IL-2 acts as autocrine factor
immune response, cell adhesion, and also tively reduce the number and size of lung for T cells, supports the development of
play a key role in pathophysiology of metastasis in both orthotropic xenografts cytotoxic T cells and stimulates NK cell
disease states such chronic inflammatory and experimental metastasis model of proliferation and cytotoxicity. However,
conditions and cancer.1 The members of breastcarcinoma.3Inaddition,antagonists IL-2 also acts to constrain lymphoid
this family include the three isoforms of of TGFβ binding to heteromeric receptor, growth and maintain peripheral tolerance.
TGFβs, β1, β2, β3; bone morphogenetic suchasasolubleFc:TGFβtypeIIreceptor The development of lymphoproliferative
proteins (BMPs) and activins. Among fusion protein (Fc:TβRII) used decoy disorders in IL-2 knockout mice are
them, TGFβ1 is the most frequently receptor has shown significant reduction tangible evidence that IL-2 can operate
overexpressed by carcinomas.2 TGFβ, the of tumor cell motility, intravasation, and asbothimmunostimulatoryandimmuno-
most potent immunosuppressive cytokine metastases in three experimental models suppressive. As immunosuppressor, IL-2
described to date, exerts severe deleterious of breast cancer. However, these treat- maintainsperipheraltolerancebyinducing
effects on several components of the ment strategies in general do not affect the generation of regulatory cells.5 For
immune system response against cancer cellular proliferation,4 which indicate thesereasons,IL-2isconsideredadouble-
cells. TGFβ abolishes the effector func- that the TGFβ blocking agents in vivo edgesword.Theversatilityofitsfunctions
tions of macrophages, B cells, cytotoxic T does not target tumor cell proliferation. isinfluencedbythecytokineenvironment
cells, dendritic cells and NK cells, where Therefore, a pro-inflammatory stimulus and the interaction with other cytokines.
TGFβ acts as negative regulator of IFNc is required to alarm the immune system Among them, TGFβ play an essential role
production via its mediators SMAD2, against proliferating tumor cells.
*Correspondenceto:JacquesGalipeau;Email:[email protected]
Submitted:10/06/11;Revised:10/14/11;Accepted:10/17/11
http://dx.doi.org/10.4161/onci.1.2.18458
224 OncoImmunology Volume1Issue2
AUTHOR'SVIEW
in sculpting IL-2 dependent signaling
pathway.
IL-2 and TGFb1, Dangerous
Liaisons Against Cancer Therapy
As suppressor of IL-2 signaling, TGFβ1
inhibitsanti-CD3andanti-CD28induced
IL-2mRNAandIL-2proteininaSmad3-
dependent manner inTcells. TGFβ1also
inhibits IL-2-induced lymphocyte prolif-
eration through a SMAD3 independent
mechanism, which may involve inactiva- Figure1.SchematicrepresentationofFISTmechanismofaction.ThroughIL-2moiety,FISTinduces
tion of phosphatase 2A (PP2A).6 theactivationofIL-2receptorexpressingimmunecells,whereasthesTbRIImoietyfunctionsas
Previous analysis of IL-2Rβ associated decoyreceptorblockingtumor-derivedTGFb-mediatedsuppressiononimmunecells.
kinaseactivation(JAK1andJAK3),aswell
as STAT5 activation by IL-2 in the
presence or absence of TGFβ show no bioactivities not only recapitulate syn- cytokine and chemokines. In summary,
evidenceofinhibitionofJak/Statpathway, ergistic effects but also possess unheralded FIST acts as an IFNc-like cytokine with
©but in ste2ad TG0Fβ-de1penden2t inhi bitLion abiophnarmaceduticalepropserties nBot seein ospecisficitycfor iIL-e2 recenptor cexpreessing .
occurs at the nuclear level on a subset of by the simple combined use of each cells. Through STAT1 activation, FIST
IL-2 target genes related to cell prolifera- moiety.9 Similarly, the fusion of IL-2 and involvesimportanttranscriptionfactorsfor
tion, including c-myc, cyclin D2 and cyclin sTβRII not only promote activation of T 1 cell-mediated immunity.
H
E. By contrast, the IL-2 mediated induc- IL-2 receptor expressing cells but also
tionofgenesinvolvedincellviabilitysuch blocks tumor derived TGFβ-mediated FIST, a Novel Angiostatic Factor
as bcl-xL and bcl-2 was not inhibited by suppression in these cell compartments
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TGFβ. Thus, the combination of TGFβ (Fig.1). The formation of new blood vessels is
and IL-2 would predictably generate a Specifically, the hyperactivation of essential for tumors to growth more
unique pattern of gene expression that STAT1 is the landmark of the mechan- 2 mm2 in volume and progress to
neither IL-2 nor TGFβ can generate ism underpinning FIST effects. STAT1 metastasis. We have found that FIST
independently.7 is key transcription factor implicated in disruptstheharmonicregulationofangio-
This dangerous liaison may lead to the development of T 1 cell-mediated genesis by two mechanisms: first, by
H
dramatic effects in the development of an immunity against tumor cells. STAT1 is sequestering active TGFβ through TβRII
effective anti-tumor response, which can a positive regulator of T-bet, the well- moiety, FIST may reduce the availability
be severely compromised by regulatory known master regulator of T 1 lineage of active TGFβ for its receptors on
H
CD4CD25cellsthatrequiresthepresence commitment and IFNc production. In endothelial cells. Second, by inducing the
of both cytokines for the induction of addition, STAT1 is also considered as production of the angiostatic chemokine
Foxp3.5 With this hypothesis inmind, we the master transcriptional regulator of CXCL10 by NK cells via STAT1 hyper-
sought to block the suppressive effects of antigen-specific T 1 cell trafficking in activation, FIST alters the formation
H
tumor-derived TGFβ in tandem with a vivo through the induction of IFNc- and/or stability of blood vessels.8 Thus
robust immune activation, and therefore inducible chemokines (CXCL9, CXCL10 FIST targets tumor derived angiogenesis
engineered a novel recombinant fusion and CXCL11).10 To complete the array at different checkpoints, which make
protein comprised of IL-2 fused to the of transcription factors required for an this molecule an effective angiostatic
extracellular domain of TGFβ receptor II, effective anti-tumor response, Smad7 is compound for cancer therapy.
sTβRII (FIST). The coupling of these also overexpressed due to STAT1 hyper-
two molecules not only recapitulates each activation. Smad7 operates along with Conclusions
moiety’s function but also gives rise to a sTβRII moiety to block TGFβ signaling.8
new cytokine-like molecule with unher- The level of FIST-mediated hyperacti- FIST is characterized by inhibiting TGFβ
alded cell biological properties.8 vation of STAT proteins is far more canonical pathway simultaneously with a
potent than the resultant combination distinctive STAT1 hyperactivation via
FIST, a New Strategy to of IL-2 receptor engagement and extra- IL-2 receptor on immune cells. Thus
Overcome Tolerance cellular depletion of active TGFβ suggest- FIST conveys a robust upregulation
and Immunosuppression ing intrinsic gain-of-function properties. of STAT1 target genes including key
Consequently, FIST-stimulated lympho- factors essential for an effective T 1
H
We have previously demonstrated that cytes reach a spectacular level of activa- cell-mediated immunity. This is the
the fusion two cytokines with different tion and production of pro-inflammatory first biological agent with the ability to
www.landesbioscience.com OncoImmunology 225
effectively couple anti-angiogenesis to propose that the strategy of coupling cytokine-like molecule may provide a
an immune antitumor response, result- functionally distinct cytokine/receptor rich and fertile source of novel biological
ing in potent anticancer properties. We pathways into a single novel fusion compounds for cancer immunotherapy.
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