cance s
Re iew
S a egies o Cance Immuno he apy Using Induced
Plu ipo ency S em Cells-Based Vaccines
B uno Be na des de Jesus 1,†, B uno Miguel Ne es 1,†, Manuela Fe ei a 2,3,* and
Sand ina Nób ega-Pe ei a 1,4,*
1Depa men o Medical Sciences and Ins i u e o Biomedicine—iBiMED, Uni e si y o A ei o,
3810-193 A ei o, Po ugal; b [email p o ec ed] (B.B.d.J.); [email p o ec ed] (B.M.N.)
2Cen e o Neu oscience and Cell Biology (CNC), Uni e si y o Coimb a, UC Bio ech, Biocan Pa k,
3060-197 Can anhede, Po ugal
3Champalimaud Resea ch, Champalimaud Cen e o he Unknown, Champalimaud Founda ion,
1400-038 Lisboa, Po ugal
4Ins i u o de Medicina Molecula João Lobo An unes, Faculdade de Medicina, Uni e sidade de Lisboa,
A . P o esso Egas Moniz, 1649-028 Lisboa, Po ugal
*Co espondence: [email p o ec ed] (M.F.); sand ina.pe [email p o ec ed] (S.N.-P.)
†These au ho s con ibu ed equally o his wo k.
Recei ed: 31 Oc obe 2020; Accep ed: 27 No embe 2020; Published: 30 No embe 2020


Simple Summa y:
E ec i e cance immuno he apies, wi h he objec i e o boos umo -speci ic
immune esponses, is a game-change in pe sonalized cance ea men . In immuno he apy,
he immune sys em is exploi ed o ecognize and des oy cance cells, and his is only possible i a ull
ecapi ula ion o umo speci ic an igens complexi y is achie ed. Pa ien -de i ed induced plu ipo en
s em cells (iPSCs) sha e se e al cha ac e is ics wi h cance (s em) cells (CSCs). The exploi a ion o iPSCs
as a sou ce o umo - and pa ien -speci ic an igens guiding he immune sys em agains cance has been
add essed ecen ly in mice. He e, we will deba e no el indings on he po en ial implica ion o cellula
ep og amming and iPSCs plas ici y o he design o no el cance immuno he apeu ic s a egies.
Abs ac :
Despi e imp o emen s in cance he apy, me as a ic solid umo s emain la gely incu able.
Immuno he apy has eme ged as a pionee ing and p omising app oach o cance he apy and
managemen , and in pa icula in ended o ad anced umo s un esponsi e o cu en he apeu ics.
In cance immuno he apy, componen s o he immune sys em a e exploi ed o elimina e cance cells
and ea pa ien s. The ecen clinical successes o immune checkpoin blockade and chime ic an igen
ecep o T cell he apies ep esen a u ning poin in cance ea men . Despi e hei po en ial success,
cu en app oaches depend on e icien umo an igen p esen a ion which a e o en inaccessible,
and mos umo s u n e ac o y o cu en immuno he apy. Pa ien -de i ed induced plu ipo en
s em cells (iPSCs) ha e been shown o sha e se e al cha ac e is ics wi h cance (s em) cells (CSCs),
elici ing a speci ic an i- umo al esponse when injec ed in oden cance models. Indeed, a i icial
cellula ep og amming has been widely compa ed o he biogenesis o CSCs. He e, we will discuss
he s a e-o - he-a on he po en ial implica ion o cellula ep og amming and iPSCs o he design o
pa ien -speci ic immuno he apeu ic s a egies, deba ing he simila i ies be ween iPSCs and cance
cells and in oducing po en ial s a egies ha could enhance he e iciency and he apeu ic po en ial
o iPSCs-based cance accines.
Keywo ds: iPSCs; cance ; ep og amming; immuno he apy; neoan igens; accines
Cance s 2020,12, 3581; doi:10.3390/cance s12123581 www.mdpi.com/jou nal/cance s
Cance s 2020,12, 3581 2 o 25
1. In oduc ion
Me as a ic solid umo s emain an un esol ed clinical challenge and one o he leading causes o
dea h. Tumo immunosu eillance is widely ecognized as an impo an mechanism o educe cance
incidence by he elimina ion o p ecance ous lesions. Tumo es ablishmen and p og ession in ol e
he p oli e a ion o hypo-immunogenic cells ha manage o e ade he immune sys em by exploi ing
immune checkpoin s, such as he p og amed cell dea h 1 (PD1) PD-ligand 1 (PDL1) axis and cy o oxic
T lymphocy e an igen-4 (CTLA-4) [1].
The use o he pa ien ’s immune sys em o elimina e neoplas ic cells has long been pos ula ed [
2
].
Howe e , only he ecen inc easing unde s anding o how cance in e ac s wi h he immune sys em
has allowed he p oposal o success ul cance immuno he apeu ic app oaches, c ea ing widesp ead
in e es and high expec a ions in he ield [
3
–
5
]. Immuno he apeu ic s a egies ha success ully ain
he immune sys em o e icien ly a ge umo s include (1) unlocking immune checkpoin s o achie e
umo ecogni ion and (2) p iming he immune sys em o use a wide epe oi e o an igens p esen ed
on umo cells. The la e includes chime ic an igen ecep o s (CAR) T-cell he apy, whe e T cells a e
gene ically enginee ed o p oduce a i icial T-cell ecep o s, showing imp essi e clinical ou comes in
ea ing pa ien s wi h elapsed o e ac o y B cell malignancies [
6
–
8
]. Al hough CAR-T cells ha e been
success ully used e en in umo s un esponsi e o con en ional he apies, many ques ions limi ing i s
clinical applica ion s ill need o be add essed. Fo ins ance, CAR-T he apies may lead o acu e cy okine
elease synd ome, issues ela ed wi h long- e m sa e y, acquisi ion o esis ance and lack o clinical
e icacy in solid umo s, issues ha need o be e ined [
9
,
10
]. Mo eo e , se e al issues pe sis wi h he
usage o T-cells, including loss o umo an igen exp ession, o - a ge oxici y and he possibili y o
in i o ans o ma ion, amongs o he s [8,11,12].
E icien umo an igen p esen a ion and s imula o y signals by an igen-p esen ing cells (APCs)
is undamen al o a sus ained ac i a ion o cy o oxic T and B-cells, and c ucial o he success
o any immuno he apeu ic app oach [
3
,
13
–
16
]. Indeed, many umo s p esen educed sel -an igen
p esen a ion due o dec eased exp ession o majo his ocompa ibili y complex (MHC)-class 1 molecules,
which esul s om he s ong selec i e p essu e imposed on umo cells in o de o e ade immuni y
du ing ea ly umo igenesis [
17
]. Cance he e ogenei y, and he p esence o undi e en ia ed cance (s em)
cells (CSCs), imposes addi ional ba ie s wi h he selec i e exp ession o an igens by di e en cance
cell popula ions wi hin a umo [
18
]. Al hough clonal neo-an igen bu den is associa ed wi h imp o ed
esponse o immuno he apy, i is cu en ly challenging o design imp o ed immuno he apeu ic
app oach as umo samples a e o en inaccessible [
19
]. Addi ionally, no el mu a ions o clonal selec ion
may lead o he esis ance o cu en immuno he apeu ic s a egies a ge ing unique an igens. Thus,
a majo challenge o cance immuno he apy is he need o de elop mo e e ec i e s a egies since,
o da e, immuno he apy only wo ks in a subse o cance s and only a ac ion o pa ien s wi h cance
espond o immuno he apy
He e, we will un eil he po en ial applica ion o cellula ep og amming and induced plu ipo en
s em cells (iPSCs)-based cance accines as no el s a egies o ackle umo he e ogenei y. Al hough ou
o scope o he p esen e iew, i is wo h o men ion ha besides di ec use o iPSCs as a no el sou ce
o cance an igens, g ea e o s ha e been pu on he ep og amming o iPSCs in o umo -speci ic
T cell, dend i ic cells (DCs), imma u e na u al-kille cells (iNKs,) and gama-del a T cells (
γδ
T) ha a e
hen applied in adop i e an i umo immuno he apies [20–28].
2. Cellula Rep og amming Is P one o E o s
In 2006, Yamanaka and colleagues challenged he cell di e en ia ion dogma, by demons a ing
ha a combina ion o he ou ansc ip ion ac o s (TFs) Oc 3/4, Sox2, Kl 4, and cMyc we e enough
o ep og am di e en ia ed mouse e al and adul ib oblas s in o iPSCs [
29
], and one yea la e ,
human iPSCs we e gene a ed [
30
,
31
]. These cells showed cha ac e is ics o emb yonic s em cells (ESCs)
including mo phology, ESC-speci ic gene exp ession and he abili y o o m all h ee emb yonic ge m
laye s as depic ed by e a oma o ma ion in SCID mice and con ibu ion o chime ic mice [
29
]. Despi e
Cance s 2020,12, 3581 3 o 25
being a majo hallma k in cell biology and p o iding unp eceden ed oppo uni y o cell he apy,
se e al challenges s ill pe sis ha limi hei cu en applica ions, including hei inhe en p ope ies
o umo igenici y, immunogenici y, and he e ogenei y [32].
iPSCs ep og amming is a e y ine icien p ocess leading o a he e ogeneous popula ion o cells
ei he ailing o eaching only pa ial ep og amming [
33
]. Addi ionally, i is no uncommon ha
ep og amed iPSCs p esen mixed esponse o di e en ia ion s imuli, jeopa dizing hei po en ial
applica ion [
34
–
36
]. Bo h gene ic and epigene ic a iabili y may con ibu e o iPSCs he e ogenei y [
37
],
as well as ecu en gene ic abe a ions [
35
,
38
–
41
]. Amongs he epigene ic ailu es is he lack o
capaci y o ully ese hei soma ic memo y, o o ully es ablish a new soma ic iden i y [
34
,
36
,
42
–
44
].
Suppo ing his obse a ion is he common de ec ion o imp in ing de ec s in iPSCs, some po en ially
hal ing iPSCs cha ac e is ics [
41
,
45
–
50
]. Rega ding he gene ic al e a ions, iPSCs may e lec he dono
gene ic backg ound. Indeed, i has been demons a ed ha dono gene ic ma e ial accoun ed o mo e
unc ional di e ences be ween iPSCs, han he cell ype [
51
]. Indeed, Kilpinen and colleagues [
52
]
desc ibed he sys ema ic gene a ion o 711 iPSC clones de i ed om 301 heal hy indi iduals, ou lining
ha 5–46% o he a ia ion be ween di e en iPSCs pheno ypes a ise om di e ences be ween
indi iduals. Al hough some o he speci ic ai s we e associa ed wi h plu ipo ency, o he s we e
po en ially associa ed wi h pa hology and umo igenici y. Mo e ecen ly Salah Mahmoudi and
colleagues [
53
] show ha ib oblas om old mice exhibi inc eased a iabili y du ing ep og amming.
By pe o ming mul i-omics p o iling o ib oblas cul u es om young and old mice, Mahmoudidi
e ealed he exis ence o ’ac i a ed ib oblas s’ ha sec e e in lamma o y cy okines, mo e p one
o ep og amming.
O he sou ces o he e ogenei y include he selec ion o clonal iPSCs ca ying speci ic mu a ions o
he acquisi ion o mu a ions du ing he ep og amming p ocess. iPSCs de i a ion s a s om a ew
cells and a iabili y was shown o be ela ed wi h p e-exis ing a ia ion in he o iginal soma ic cells,
ei he con ibu ing o highe o lowe ep og amming a es [
38
,
54
–
59
]. Se e al pa ien -speci ic soma ic
mu a ions impac on iPSCs ep og amming [
60
], aising impo an issues when pa ien -de i ed iPSCs
a e equi ed. Those include dys unc ion o he mi ochond ial espi a o y chain [
61
,
62
] o ch omosomal
abno mali ies [
63
,
64
]. Fu he mo e, du ing he
in i o
ep og amming p ocess, iPSCs may acqui e
(addi ional) soma ic mu a ions which could ela e o he ep og amming s a egy. iPSCs de i a ion
does no only co ela es wi h p e-exis ing mu a ions bu could also lead o “de no o” mu a ions [
51
,
65
];
due o he complexi y o he ep og amming p ocess is was e i ied ha iPSCs acqui e mo e poin
mu a ion han ESCs. One example is he oxida i e s ess linked mu a ions acqui ed du ing cellula
ep og amming [66,67].
As men ioned, he ep og amming p ocess o he subsequen expansion in cul u e ep esen
addi ional sou ce o iPSCs he e ogenici y. I was p e iously shown ha 17 di e en human ESCs lines
main ained in di e en labo a o ies p esen 843 copy numbe a ia ions (CNV) [
68
]. In e es ingly,
se e al o he genes de ec ed wi hin CNV si es had al e ed exp ession and we e unc ionally linked o
cance . These esul s suppo he hypo hesis ha cellula he e ogenei y may lead o he acquisi ion o
cance like p ope ies. One example linking iPSCs o cance biogenesis is he abno mal exp ession
o TERT, which ac i i y is mainly es ic ed o s em cells in he adul issues [
69
–
71
]. As iPSCs can
be gene a ed om soma ic cells, hey show g ea po en ial o de eloping pa ien speci ic disease
modeling, which can be used o s udy he unde lying mechanisms and no el ea men s o cance [
72
].
Simila ly,
in i o
ep og amming is also p one o he e ogenei y.
In i o
iPSCs ha e an
unp eceden ed capaci y o o m emb yo-like s uc u es, including he h ee ge m laye s o he
emb yo and ex aemb yonic issues, s ill only a small pe cen age o cells could gi e ise o such
s uc u es [
73
]. O no ewo hy, and using an assay whe e GFP-exp essing iPSCs and ESCs we e
mic oinjec ed in o he mo ula and he esul ing blas ocys s we e examined, Abad e al obse ed
ha iPSCs gene a ed
in i o
con ibu ed o he ophec ode m wi h a ema kable e iciency (56%),
which was in con as o ESCs (0%) [73].
Cance s 2020,12, 3581 4 o 25
iPSCs Sha e Simila i ies wi h Cance S em Cells
CSCs a e subpopula ions o cance cells wi h s em cell ea u es as sel - enewal abili y and
mul i-lineage di e en ia ion ha d i e umo g ow h and he e ogenei y. Impo an ly, CSCs ha e been
in oked as he main d i e s o me as a ic dissemina ion, elapse and he apeu ic esis ance [
74
,
75
].
Malignan and me as a ic umo s, which e ade immune clea ance, show a highe incidence o
cance -speci ic soma ic mi ochond ial DNA (m DNA) mu a ions in p o ein-coding o RNA-coding
egions [
76
] and exp ession o s emness genes [
75
], sugges ing ha lowe immune clea ance is
associa ed wi h inc ease cance -speci ic mu a ions and exp ession o s emness ma ke s. Simila ly,
o ESCs, iPSCs also sha e a numbe o cha ac e is ics wi h CSCs including sel - enewal and
p oli e a ion, exp ession o s em cell ma ke s and al e ed me abolism. The simila i ies be ween
e al de elopmen and cance has long been ecognized, ollowing he disco e y o onco e al p o eins
(such as
α
- e opo ein, ca cinoemb yonic an igen, human cho ionic gonado opic, o a e iew see [
77
]),
which a e umo -associa ed an igens (TAAs) exp essed du ing emb yonic de elopmen and e-acqui ed
in adul s du ing cance [
78
]. Human iPSCs sha e gene ic and ansc ip omic signa u es wi h cance
issues, including se e al cance - ela ed genes and mo e han 100 human TAAs and umo -speci ic
an igens (TSAs), which a e p o ein ma ke s ha can be ecognized by he immune sys em [79,80].
In con as o di e en ia ed cells, cance cells and ESCs e ain he abili y o e-en e he cell
cycle and p oli e a e and i does no come o a su p ise ha common me abolic s a egies ha uel
anabolic cell g ow h a e adop ed. Cance cells and ESCs p esen inc eased glycoly ic lux which
sus ains high a es o cellula p oli e a ion by apidly gene a ing adenosine iphospha e (ATP),
whe eas mi ochond ia is mainly used o anabolic p oduc ion, a phenomenon known as he Wa bu g
e ec [
81
–
83
]. Howe e , ecen e idence sugges s ha ene ge ics o slow-cycling and he apy- esis an
CSCs di e om he bulk p oli e a i e umo , ha la gely ely in glycolysis. CSCs p esen an inc eased
dependency in OXPHOS and mi ochond ial espi a ion and his ulne abili y can be exploi ed o
umo e adica ion [
84
]. Fo ESCs, he main me abolic p og am adop ed and ene ge ic uel used o
ATP p oduc ion seems o ely on he plu ipo ency s a e [
81
]. When compa ed o p imed, nai e ESCs
p esen ele a ed mi ochond ial unc ion, inc eased OXPHOS, and a lowe le el o glycolysis whe eas
p imed ESCs p esen highe m DNA copy numbe and mo e ma u e mi ochond ia [81,82].
As o oncogenesis, cellula ep og amming o plu ipo ency induces a global me abolic emodeling
ha leads o a p og essi e ansi ion om soma ic oxida i e me abolism o glycolysis, wi h an
inc ease in glycoly ic a e and lac a e p oduc ion oge he wi h a dec ease in cellula espi a ion and
o he mi ochond ial adap ions [
85
,
86
]. Me aboli es unc ion goes beyond se ing as subs a es o
ene gy p oduc ion and anabolic g ow h and can de e mine he balance be ween CSCs and ESCs
sel - enewal and di e en ia ion. Many me abolic in e media es (as ace yl-CoA, S-adenosylme hionine,
α
-ke oglu a a e) se e as obliga o y subs a es o co ac o s o ch oma in-modi ying enzymes,
impac ing epigene ic egula ion and gene exp ession [
82
]. Fo ins ance, epide mal CSCs a oid
epigene ically d i en di e en ia ion by shu ing down endogenous se ine syn hesis and becoming
dependen on ex acellula se ine [
87
]. De no o se ine syn hesis s imula es
α
-ke oglu a a e-dependen
dioxygenases ha emo e he ep essi e his one modi ica ion H3K27me3, ac i a ing di e en ia ion
and blocking squamous cell ca cinoma g ow h [
87
]. Lipid me abolism is also linked o s em cell
plu ipo ency. Fa y acid syn hesis is c i ical o ESCs plu ipo ency and cellula ep og amming in o
iPSCs [
88
]. Likewise, s imula ion o de no o lipogenesis by lipid dep i a ion induces a nai e-like
s a e in human PSCs by enhanced his one ace yla ion and dec eased DNA me hyla ion which mimics
ERK inhibi ion [
89
]. These s udies highligh he po en ial o nu ien manipula ion as a s a egy o
induce me abolic-d i en epigene ic and gene exp ession changes unde lying (CSCs and iPSCs) s em
cell a e decisions.
Fo no mal o CSCs o main ain hei s emness, hey mus balance bo h in insic and ex insic
signals, main aining p oli e a ion while inhibi ing unwan ed di e en ia ion and bypassing immune
ecogni ion. Epigene ic egula o s a e e ec o s o hese inpu s wi h al e a ions o en leading o cell
dea h, o oncogenic ans o ma ion and g ow h [
90
,
91
]. Cance cells a e gene ically and epigene ically
Cance s 2020,12, 3581 5 o 25
plas ic, ha ing he po en ial o egain benign cell unc ions ia e-exp ession o lineage-speci ic
genes [
90
,
92
]. Recen ly iPSCs ha e been p oposed as a no el me hod o s udying ca cinogenesis
h ough cance cell ep og amming. A numbe o human cance cell lines and p ima y samples
ha e been used o gene a e iPSCs, in an a emp o ecapi ula e he mechanisms unde lying cance
de elopmen and as a s a egy o induce ansi ion om malignancy o benigni y [
6
,
90
,
93
]. Since he
ini ial desc ip ion o ep og amming using he ou Yamanaka TFs [
29
,
30
], se e al modi ica ions in
he ep og amming p o ocol aiming a inc easing e iciency ha e been desc ibed. Many o hose,
ac commonly in cance -associa ed pa hways and may con ibu e o umo p og ession, such as
down- egula ion o he umo supp esso s p53 o p16/nk4a-ARF [
94
,
95
]. In line wi h his, we and
o he s ha e p e iously demons a ed ha Zeb2, a ac o in ol ed in epi helial o mesenchymal
ansi ion (EMT) and me as a ic po en ial [
96
–
98
], is an impo an ba ie limi ing he ep og amming
o aged ib oblas s [
99
]. As o CSCs, iPSCs ha e he po en ial o in ini e p oli e a ion and in ce ain
scena ios, umo igenic p ope ies ha e been a ibu ed. O no ice, all o he 4 TFs o iginally included in
he Yamanaka cock ail ha e p o ed oncogenic po en ial [
32
], especially c-Myc which is one o he mos
equen ly mu a ed genes in human cance s. Indeed, app oxima ely 20% o he chime ic mice o sp ing
made by iPSCs-de i ed om 4TFs ep og amming de eloped umo s a ibu able o eac i a ion
o he c-Myc ansgene [
100
]. Besides, ampli ica ion o genomic and m DNA mu a ions du ing he
ex ensi e
in i o
iPSCs cul u ing may ep esen ano he sou ce o umo igenici y and exp ession o
immunogenic p o eins [
101
,
102
]. Simila ly, ophec ode m ma ke s de ec ed in
in i o
iPSCs a e also
linked o he pa hobiology o cance (e.g., Fg 2) [73].
CSCs ha e he abili y o bo h sel - enewal and di e en ia ion and CSCs su i e chemo he apy
ha e been shown o be able o e-es ablish umo s [
75
,
103
]. While i s o igin is no ully known, i has been
sugges ed ha CSCs could a ise as a esul o mu a ions in s em, ansien -ampli ying, di e en ia ed o
cance cells leading o acquisi ion o malignan and/o s em cell p ope ies [
92
]. Mo eo e , a numbe
o s udies also sugges he exis ence o plas ici y wi hin cance and s em cell’s compa men s [
92
].
Fo ins ance, in b eas cance , no mal and CSCs-like cells can a ise de no o om mo e di e en ia ed
cell ypes e ealing ha mamma y s em cells encompass bidi ec ional in e con e sions be ween
s em and non-s em compa men s [
104
]. A i icial (o
in i o
) cellula ep og amming has also been
widely compa ed o he biogenesis o CSCs [
90
]. T ansi o y induc ion o he 4TFs in mice is able o
p oduce
in i o
ep og amming wi hin issues wi h o ma ion o e a omas and ci cula ing iPSCs in he
blood [
73
]. Whe he ep og amming o soma ic di e en ia ed cells in o iPSCs is a (na u ally) occu ing
p ocess in i o and can con ibu e o cance and s em cell popula ions emains o be elucida ed.
3. iPSCs as Whole-Cell Cance Vaccines
Ou g owing knowledge o umo immunobiology, which is e lec ed by he cons an inc ease
complexi y o he immunoedi ing concep has led, in he las decade, o a pa adigm shi in he
ea men o nume ous cance s [
105
–
107
]. Blockade o he immune checkpoin s ep esen a ema kable
b eak h ough in cance immuno he apy whe eas o he s a egies, such as TAAs/TSAs and DCs accines,
s a o ise as alid con ibu es o push o wa d his h illing ield [
108
]. He e, au ologous whole umo
cells accines seem o add ess he umo he e ogenei y ca ea . Howe e , his app oach equi es access
o su icien iable biopsy ma e ial and can only be used in a he apeu ic se ing, wi hou possibili y o
design p ophylac ic s a egies.
As p e iously de ailed, cance ans o ma ion is coupled o he appea ance o s em-like ea u es,
d i ing he idea ha s em/emb yonic issues may ha bo he same an igens p esen in umo s. In his
con ex , ESCs and iPSCs ha e been ex ensi ely es ed in an i- umo immuniza ion p o ocols [
79
,
109
,
110
].
The seminal expe imen s o Geo ge Schöne demons a ing ha immuniza ion wi h emb yonic issue
gene a es speci ic an i umo esponses da e back a cen u y ago [
111
]. Since hen, nume ous p e-clinical
s udies ha e shown ha accina ion wi h emb yonal ma e ial p e en no only he g ow h o
ansplan able umo s as well as umo igenesis caused by i al and chemical agen s ( e iewed in [
112
]).
Ne e heless, e hical cons ains associa ed wi h he accessibili y o ESCs, he educed epe oi e o

Cance s 2020,12, 3581 6 o 25
ma ching cance an igens and unwan ed immune esponses gene a ed by human leukocy e an igen
(HLA) incompa ibili y in allogenic accine se ings, limi ed i s clinical applica ion [
113
]. In his
ega d, au ologous iPSCs-based accines may add ess hese limi a ions p o iding an al e na i e
s a egy. The i s epo o he use o iPSCs as a whole-cell cance accine comes om Li and
collabo a o s, whe e hey compa e he e icacy o human iPSCs and ESCs lines as immunizing agen s
in a ansplan able mouse colon ca cinoma model [
114
]. Al hough accina ion wi h bo h human ESCs
and iPSC lines induced signi ican expansion o umo -speci ic IFN
γ
- and IL-4-p oducing T cells,
only human ESC cells inhibi ed umo g ow h. The he e ogenei y o onco e al an igens exp ession as
well as he accumula ion o myeloid-de i ed supp esso cells (MDSCs) in iPSCs-immunized g oups
we e p oposed as possible explana ions o he dis inc an i- umo p o ec ion con e ed by iPSCs and
ESCs [
114
] (Table 1). In e es ingly, no e idence o au oimmuni y was obse ed, sugges ing ha he
an igens p esen in ESCs a e di e en om he an igens p esen ed in adul s em cell niches.
One o he i s e idences ha au ologous iPSCs could elici an immunogenic esponse was
p esen ed by Zhao e al., whe e ansplan a ion o imma u e C57BL/6 (B6)-de i ed iPSCs ( ep og ammed
om mouse emb yonic ib oblas s) induced T cell in il a ion, issue damage and eg ession o e a omas
in syngeneic ecipien mice [
115
] (Table 1). In his s udy, T cell in il a ion was obse ed in mos
e a omas o med by he B6 iPSCs in syngeneic mice, some o which also exhibi issue nec osis and an
appa en eg ession a 40 days pos -implan a ion [
115
], suppo ing ha iPSCs a e immunogenic in
syngeneic ecipien s.
The concep o iPSCs-based an icance accine was u he e ined by Koo eman by using
i adia ed au ologous iPSCs in combina ion wi h he TLR9 agonis , CpG oligodeoxynucleo ide [
80
]
(Table 1). The use o au ologous iPSCs allowed o minimize alloimmuni y s imula ed by MHC
misma ches and he addi ion o he immunos imula o y adju an CpG p omo ed he ma u a ion o
APCs such as DCs. In a p e en i e accina ion se ing, injec ion o i adia ed au ologous iPSCs plus
CpG esul ed in he p oduc ion o umo - eac i e an ibodies, expansion o e ec o /memo y helpe
T cells and ma u e DCs as well as in a signi ican dec ease in CD4
+
CD25
+
FoxP3
+
egula o y T cells
(T- egs). This a o able CD8
+
T/T- egs a io in accina ed mice esul ed in he ejec ion o ansplan ed
b eas cance , melanoma, and meso helioma umo cells [
80
]. Analysis o ea ly in a- umo in il a es
e ealed inc eased numbe s o accine-elici ed B and T clones exp essing IL-2, IL-4, and IL-5. Mo eo e ,
adop i e ans e o T cells om immunized animals o naï e ecipien s con e ed umo p o ec ion,
p o iding clea e idence ha he obse ed e ec was being media ed by T cells. When es ed in a
clinically ele an scena io (i.e., he apeu ic adminis a ion in animals bea ing es ablished melanomas),
he iPSCs +CpG accine ailed o educe umo g ow h. Recen ly, ano he s udy epo ed ha
iPSCs he apy was ine ec i e in educing melanoma umo g ow h p obably due o he es ablished
immunosupp essi e mic oen i onmen [
116
]. Howe e , as an adju an he apy a e melanoma
esec ion, iPSCs accines eac i a ed he immune sys em in elimina ing aces o melanoma cells.
This ejec ion was media ed h ough IL-4 exp essing B-cells, TNF-
α
-exp essing CD11b
+
GR1
hi
myeloid
cells, and a educ ion o umo -p omo ing Th17 cells [
80
]. This seminal obse a ion c ea ed a g ea
en husiasm gi en ha i showed iPSCs as a TSAs- and TAAs sou ce, eadily a ailable a ime o umo
esec ion, allowing o p ime and eac i a e an i umo immuni y and p e en ing elapses.
Addi ional s udies co obo a ed he po en ial o iPSCs-based an icance accines in mul iple
umo models. A accine composed o Hype -IL6 (H16) gene-modi ied melanoma cells admixed
wi h allogenic iPSCs was shown o cause supe io ex ension disease- ee su i al, and long- e m
o e all su i al in melanoma-challenged C57BL/6 mice when compa ed o modi ied cells alone o
H16 modi ied cells plus ESCs [
117
] (Table 1). Mice accina ed wi h mixed-iPSCs accine shown,
in he injec ion si e and spleen, inc eased numbe s o in lamma o y monocy es, ac i a ed CD4
+
T
cells and memo y CD4
+
T and CD8
+
T cells, while he e was a dec ease in he pe cen age o MDSCs.
iPSCs immuniza ion also led o inc eased pe cen ages o in lamma o y monocy es, DCs and NKs in he
umo mic oen i onmen (TME) as well as supe io le els o IFN-
γ
and IL-12p70, causing concomi an ly
a educ ion o in il a ing T egs [
117
]. Mo eo e , Gabka-Buszek and colleagues demons a ed he
Cance s 2020,12, 3581 7 o 25
e ec i eness o melanoma accines composed o umo cells mixed wi h melanoma s em-like cells o
iPSCs. In pa icula , a accine con aining syngeneic iPSCs and B16F10 cells, signi ican ly inhibi ed
umo g ow h and inc eased mouse su i al [117].
Addi ionally, in a humanized-mice model o lung cance , accina ion wi h iPSCs +CpG was
shown o inc ease he pe cen age o splenic APCs and cy o oxic T cells, ci cula ing e ec o /memo y
CD4
+
and CD8
+
T cells and umo -in il a ing CD8
+
T cells, while dec easing T egs [
118
] (Table 1).
This immune landscape suppo ed an e ec i e supp ession o umo g ow h, and he cen al ole o
umo an igen-speci ic T cells was demons a ed by he p o ec ion con e ed h ough he adop i e
ans e o spleen T cells om he accine p eimmunized mice o un accina ed ecipien s. The p o ec i e
immuni y elici ed by iPSCs was p oposed o be due o he gene exp ession pa e n sha ed be ween
iPSCs and lung adenoca cinoma s em cells [118].
Cance s 2020,12, 3581 8 o 25
Table 1. Immunogenici y esponses elici ed by induced plu ipo en s em cells (iPSCs) whole-cell cance accines in mouse models.
Species Cell o
O igin
Rep og amming
Condi ions iPSCs S a e Local o
Eng a men
Immunogenici y
Tes Immune Response Immunogenic
P o eins
Tumo
Ta ge ed S udy
Homo
sapiens
Fe al lung
ib oblas
line IMR90
Len i i us
exp essing 6F 1TTZ1 cell line sc 2Te a omas Tumo -speci ic IFN-γ-and
IL-4-p oducing T cells
Onco e al
an igens
Colon
ca cinoma [114]
Mus
Musculus MEFs 3
Re o i us
exp essing 3F 4
and 4F 5, 4F
non-in eg a i e
episomal ec o
SSEA-1 sc (hind leg)
Te a omas
IFN-γ
eleasing
assay in i o
CD4+helpe T CD8+
cy o oxic T
Ho mad1
Zg16 na 6[115]
Mus
Musculus
Fib oblas s
om FVB,
C57BL/6J,
and CBA/J
mice
Codon-op imized
mini-in onic
plasmid
con aining 4F
SSEA-1 sc ( lank) Te a omas
Inc ease in e ec o /memo y
helpe T cells, ma u e DCs,
IL-4-exp essing B cells,
TNF-αexp essing myeloid
cells; dec ease in T egs and
Th17 cells
Onco e al
an igens
B eas cance ,
melanoma,
and meso helioma
umo cells
[80]
Mus
Musculus MEFs
Nucleo ec ion
wi h plasmid
coding 4F
SSEA-1;
Epcam,
E-cadhe in,
NANOG,
alkaline
phospha ase
sc na
In lamma o y monocy es,
ac i a ed CD4+T cells,
memo y CD4
+
T and CD8
+
T;
umo in il a ing DCs, NKs,
in lamma o y monocy es;
dec ease in T egs and MDSCs
TAAs 7/TSAs
8sha ed wi h
CSCs 9
Melanoma [117]
Homo
sapiens
Fib oblas s
na na sc na
Splenic APCs and cy o oxic T
cells; ci cula ing
e ec o /memo y CD4+and
CD8+T cells; umo
in il a ing CD8+T cells;
dec ease in T egs
TAAs/TSAs
sha ed wi h
CSCs
Lung cance [118]
Mus
Musculus
Tail- ip
ib oblas s
Re o i us
exp essing 3F
Endo ac o s;
colony
o ma ion
assays
sc
IFN-γ
eleasing
assay in i o
Inc ease in ac i a ed CD8+
and CD4+T cells TAAs/TSAs
Panc ea ic
duc al
adenoca cinoma
[119]
1
6F (Oc 3/4/Sox2/Lin28/Kl 4/Nanog/c-Myc);
2
subcu aneous;
3
mouse emb yonic ib oblas s;
4
3F (Oc 4/Sox2/Kl 4);
5
4F (Oc 4/Sox2/Kl 4/cMyc);
6
non-add essed;
7
umo associa ed
an igens; 8 umo speci ic an igens; 9cance s em cells.
Cance s 2020,12, 3581 9 o 25
Al hough he di e en ia ion o iPSCs is epo ed o esul in loss o immunogenici y [
80
,
120
,
121
],
iPSCs-de i ed panc ea ic umo cells we e ecen ly p oposed as possible whole cell- accines o p e en
o delay panc ea ic duc al adenoca cinoma (PDAC) in KPC ansgenic mice [
119
] (Table 1). Tumo cells
we e c ea ed by in si u gene edi ing o heal hy ib oblas -de i ed iPSCs ia in oduc ion o K as and
p53 mu a ions. In con as o non ans o med iPSCs, he ansc ip ome o ep og amed cells e ealed
highly simila gene exp ession p o iles o ansgenic mouse-de i ed umo cell lines, alida ing he
model as a sou ce o TAAs and TSAs. To inc ease he immunogenici y, iPSC-de i ed panc ea ic umo
cells we e in ec ed wi h adeno i us o accinia i us p io inocula ion. The p ophylac ic accina ion
o KPC ansgenic mice wi h adeno i us-in ec ed ep og amed iPSCs ollowed by boos ing wi h he
accinia-in ec ed cells was shown o e ec i ely delay PDAC de elopmen , signi ican ly p olonging
mice su i al. Tumo con ol was associa ed wi h inc eased le els o ac i a ed CD8
+
and CD4
+
T
ound in lymph nodes, spleen, and umo in il a es. Tumo speci ic immuni y was howe e los o e
ime and in il a ion o CD8
+
T cells wi hin umo s was minimal 3 mon hs a e immuniza ion [
119
].
O e all, hese s udies sugges ha au ologous iPSCs elici a speci ic an i- umo al esponse, highligh ing
he po en ial use o iPSCs-based accines o cance he apy.
3.1. Lessons F om ESCs: The Immune Response o Plu ipo en Cells
Pionee s udies using ESCs o cance accina ion shown e idence o p o ec i e e ec s only
when ea ly bu no la e emb yonic issues we e used and his was a ibu ed o he exp ession o
onco e al an igens [
77
,
112
,
114
]. Al hough some s udies ha e used ESCs in an allogeneic ans e ,
due o he limi ed a ailabili y, ESCs cells a e mo e likely o be ans e ed o an un ela ed hos which
may igge an alloimmune esponse. Thus, al hough indis inguishable om allogeneic esponses,
an immune esponse o onco e al an igens is gene a ed when ESCs a e ans e ed ei he allogeneically
o syngeneically.
The immunogenic esponse elici ed by iPSCs was sugges ed o con as wi h ESCs,
whe e ansplan a ion in o syngeneic ecipien mice esul ed in e icien o ma ion o e a omas wi hou
e idence o immune ejec ion (as indica ed by he lack o de ec able CD4
+
T cell in il a ion) [
115
].
ESCs possess immune p i ileged p ope ies and ha e he capaci y o inhibi immune ac i a ion.
Howe e , he immunogenici y o ESCs may ha e been unde es ima ed [
122
]. Undi e en ia ed s em
cells and de i a i es ha e been shown o induce an immune esponse in i o ha in ol es cy o oxic
T lymphocy es, helpe T cells, and NKs [
123
–
125
]. Indeed, ESCs exp ess NK cell–ac i a ing ligands
and a e suscep ible o NK cell ecogni ion and a ack [
126
,
127
] al hough some s udies claim ha
undi e en ia ed ES cells a e esis an o NK cell a ack [128–130].
The e a e wo main classes o polymo phic MHC molecules, human leukocy e an igen (HLA) in
humans, exp essed by cells ha a e able o p esen an igens [
131
]. While mouse ESCs exp ess mRNA o
MHC molecules, bu no he co esponding p o eins [
132
–
134
], human ESCs exp ess a iable, albei low
le els o HLA class I molecules and almos unde ec able le els o HLA class II [
125
,
129
,
132
,
133
,
135
–
137
].
As undi e en ia ed ESCs exp ess low le els o MHC-I and co-s imula o y molecules, ansplan ed
g a -de i ed an igens may be p ocessed di ec ly by APCs o indi ec ly h ough APCs ac i a ion
o T cells [
129
,
138
,
139
]. In his con ex , he immune esponse o ansplan ed ESCs may in ol e
3 main de elopmen al s ages. The i s s age occu s du ing which ecipien MHC class II– es ic ed
CD4
+
T cells ecognize an igens p esen ed by ecipien APCs and elease p oin lamma o y cy okines.
The second s age occu s when sel - es ic ed CD4
+
T cells help o gene a e cy o oxic T lymphocy es
ha can ecognize in ac MHC class I molecules. The hi d s age is an ibody esponse, du ing which
alloan igen-p imed CD4+T cells deli e ac i a ing signals o B cells.
The low le els o MHC an igens exp essed by ESCs a e belie ed o con ibu e o T cell ecogni ion
a oidance e en hough
in i o
ESCs could ins ead be ecognized and suscep ible o killing by
NKs [
126
,
132
,
136
]. Independen ly o he immunologic condi ion o ESCs ans e (syngeneic, allogeneic
and xenogeneic), he inna e immune esponse in ol ing NKs plays a c i ical ole agains ansplan ed
ESCs. Mo eo e , MHC exp ession can be inc eased du ing ESCs di e en ia ion and in he p esence
Cance s 2020,12, 3581 16 o 25
Acknowledgmen s:
We since ely apologize o colleagues whose wo k has no been included in his Re iew due
o space limi a ions.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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