Biomedical Engineering Reference
In-Depth Information
signals, uni-directionally, on liver, pancreas, breast, brain,
and colon cancer cells.
In similar manner, other paradigmatic SCP set forth
earlier in this chapter would be characterized as follows:
systems biology vantage point [106]. While the discourse
has largely centered on metabolic enzymes, along with
signaling, structural, and nucleic acid binding proteins,
the receptor-ligand duality of cell surface proteins is essen-
tially just another form of moonlighting.
The fact that cell surface proteins moonlight, manifesting
bidirectional signaling potential, has clear implications
when predicting and deciphering SCP effects. It translates
into an SCP's capacity, via either of their chimerized
components, to at once serve as an intercellular signal
blocker, a reverse-signaling ligand, and a competitive inhib-
itor of the receptor function. In turn, this array of functional
potentialities, mediated by both ends of a single fusion
protein, serves to amplify cellular reach and therapeutic
efficacy.
This particular coding system does not purport to convey
all the mechanisms of action associated with a given SCP,
for example, CTLA-4-FasL's ability to prevent the upregu-
lation of c-FLIP associated with T-cell activation. That is not
to say that this or other functional coding systems could not
be adapted to capture deeper mechanistic features that tie
into signal converter functionalities and efficacy. Even for
those SCP that have been studied most intensively to date,
the mechanistic tree is almost certain to extend new
branches. Functional richness of SCP will continue to
emanate from both the broad tissue distribution and func-
tional pleiotropism of their surface molecular targets.
CTLA-4
FasL
:
SCP
j
t2c
f
apcø act Teff
neo
=
c
f
dcø Treg
g
þ
c
=
ud
f
tumor
>
hemat
g
CD40
FasL
:
SCP
j
c
=
bd
f
act T eff
;
tumor
>
hemat
g
FasL, this label conveys that it is an SCP
with three well-defined functional modes: (1) a TSCP mode,
in which it converts an intercellular signal exchanged
between two cells, an APC and an activated effector T
cell; (2) a neoexpression mode, in which it promotes neo-
expression on DC surfaces of a regulatory T-cell stimulatory
signal; and (3) a CLBP mode in which it directs loop-back
signals, uni-directionally, on hematopoietic tumor cells. In
the case of CD40
For CTLA-4
FasL, the designation specifies that there is
in essence one well-characterized signaling mode—a
bidirectional signaling CLBP mode—that plays out in
two distinct cellular contexts, that is, activated, effector
T cells and hematopoietic tumor cells.
Clearly, the functional bar code associated with a given
SCP will evolve over time, often substantially, as new
functional capabilities are uncovered. The inherent flexibil-
ity of such a coding system bypasses the reductionist trap
when trying to pigeonhole individual SCP into monolithic
functional categories. Since this nomenclature pegs func-
tions to particular cellular contexts, it conveniently accom-
modates the functional heterogeneity that follows from the
pleiotropic expression, across diverse cell types, of so many
of the surface molecules targetable by SCP.
Embedded within this SCP code is directionality of
signaling, which implicitly touches on a growing appreci-
ation for Escher-like surface receptor-ligand functional
duality. That is, many surface proteins initially labeled as
“receptors” turn out to additionally act as signal-sending
ligands, and reciprocally, many characterized at the outset as
intercellular signaling ligands prove to be able to reverse
signal in a signal-receiving mode. Among the continuously
expanding compendium of molecular pairs associated with
bidirectional signaling are CD40L (CD154):CD40
(TNFRSF5); OX40L (CD252; TNFSF4):OX40 (CD134);
GITRL (TNFSF18):GITR (CD357; TNFRSF18),
CD80/86:CTLA-4/CD28 and CD70:CD27 (TNFRSF7).
Indeed, bidirectional signaling seems to be more a rule
than an exception. The growing appreciation that “receiver”
proteins can send and “sender” proteins can receive high-
lights the frequent arbitrariness of the “receptor” and
“ligand” labels, which does the disservice of tunneling
thinking when it comes to fusion protein design.
The term “moonlighting protein” has been applied to
individual proteins displaying unrelated functional propert-
ies, which are of special interest when viewed from the
30.10 EXPANDING THE CATALOG
OF INHIBITORY SCP
The costimulator receptor
coinhibitor (CoSR
CoI) TSCP
motif exemplified by CTLA-4
FasL, along with the more
general
inflammatory signal blocker
lymphoid inhibitor
TSRP motif featured in Fn14
TRAIL, provide robust tem-
plates for generating additional T-cell-directed SCP inhibi-
tors. In mixing and matching CoSR and CoI components,
one can draw upon a diverse set of known costimulator
receptors {for example, CD28, ICOS (CD278), OX40
(CD134), 4-1BB (CD137), GITR (TNFRSF18), and
CD27; reviewed in References [107-110], and a more
limited set of coinhibitor options [FasL (CD95L; CD178),
TRAIL (CD253), PD-L1 (B7-H1; CD274), PDL2 (B7-DC;
CD273), HVEM (TNFRSF14) [111-113] ]. An expanded
SCP palette, encompassing more chimeric CoSR
CoI
permutations, will enable preferential targeting of selected
T-cell subsets, corresponding to different lineage, activation,
and differentiation states. While the cell surface molecular
fingerprints of T-cell subsets are by no means discrete, they
do offer some opportunity for configuring SCP with a certain
degree of subset selectivity and leveraging differences in
costimulator requirements and coinhibitor sensitivities. Fur-
thermore, since the pivotal pathogenic T cells vary for
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