cance s
Re iew
In eg a ing he Tumo Mic oen i onmen in o
Cance The apy
Sabina Saneg e 1,†, Fede ico Lucan oni 1,†, Rebeca Bu gos-Panade o 1,2, Luis de La C uz-Me ino 3,
Rosa Nogue a 1,2,* and TomásÁl a o Na anjo 2,4,5,*
1Depa men o Pa hology, Medical School, Uni e si y o Valencia—INCLIVA Biomedical Heal h Resea ch
Ins i u e, 46010 Valencia, Spain; ssaneg [email p o ec ed] (S.S.); [email p o ec ed] (F.L.);
[email p o ec ed].es (R.B.-P.)
2Low P e alence Tumo s, Cen o de In es igación Biomédica en Red de Cánce (CIBERONC),
Ins i u o de Salud Ca los III, 28029 Mad id, Spain
3Depa men o Oncology, Hospi al Uni e si a io Vi gen Maca ena, 41009 Se ille, Spain;
[email p o ec ed]
4Depa men o Pa hology, Hospi al de To osa Ve ge de la Cin a, Ca alan Ins i u e o Heal h,
Ins i u d’In es igacióSani à ia Pe e Vi gili (IISPV), 43500 To osa, Spain
5Depa men o Mo phological Science, Medical School, Ro i a i Vi gili Uni e si y, 43201 Reus, Spain
*Co espondence: nogue a@u .es (R.N.); al a o.eb [email p o ec ed] (T.Á.N.);
Tel.: +34-2304-977519104 (T.Á.N.)
†These au ho s con ibu ed equally o his wo k.
Recei ed: 18 May 2020; Accep ed: 18 June 2020; Published: 24 June 2020
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Abs ac :
Tumo p og ession is media ed by ecip ocal in e ac ion be ween umo cells and
hei su ounding umo mic oen i onmen (TME), which among o he ac o s encompasses he
ex acellula milieu, immune cells, ib oblas s, and he ascula sys em. Howe e , he complexi y
o cance goes beyond he local in e ac ion o umo cells wi h hei mic oen i onmen . We a e on
he pa h o unde s anding cance om a sys emic iewpoin whe e he hos mac oen i onmen also
plays a c ucial ole in de e mining umo p og ession. Indeed, g owing e idence is eme ging on he
impac o he gu mic obio a, me abolism, biomechanics, and he neu oimmunological axis on cance .
Thus, ex e nal ac o s capable o in luencing he en i e body sys em, such as emo ional s ess, su ge y,
o psychosocial ac o s, mus be aken in o conside a ion o enhanced managemen and ea men
o cance pa ien s. In his a icle, we e iew p ognos ic and p edic i e bioma ke s, as well as hei
po en ial e alua ion and quan i a i e analysis. Ou o e a ching aim is o open up new ields o s udy
and in e en ion possibili ies, wi hin he amewo k o an in eg al ision o cance as a unc ional
issue wi h he capaci y o espond o di e en non-cy o oxic ac o s, ho monal, immunological, and
mechanical o ces, and o he s inducing s oma and umo ep og amming.
Keywo ds:
immune he apy; me abolism; mic obio a; bioma ke disco e y; p ognos ic ools; i amin
D3; s omal ep og amming; mi ochond ia; mechano ansduc ion; me o min
1. In oduc ion
Since he 1980s, cance esea ch has ocused on de eloping new he apeu ic agen s a ge ing DNA
al e a ions and he sea ch o a sui able cu e, a he han unde s anding cance as an in eg a ed sys em
composed o se e al modules. To da e, he abili y o cance cells o su i e o a p olonged ime is
s ill incomple ely unde s ood. In his con ex , we a e beginning o include he ole o s em cells in
he umo e olu ion p ocess and o poin ou cellula pa hways as a physiological adap i e p ocess
like a “wound ha ne e heals” [
1
]. The idea ha cance o igina es as a consequence o a malignan
Cance s 2020,12, 1677; doi:10.3390/cance s12061677 www.mdpi.com/jou nal/cance s
Cance s 2020,12, 1677 2 o 24
cellula de elopmen can be conside ed in a mul i-le el amewo k whe e di e en p ocesses such as
senescence, egene a ion, wound healing and p oli e a ion play a key ole.
The majo i y o umo s ha e a he e ogeneous cellula popula ion, and he ision ha cance
o igina es om clonogenic expansion om a single mu a ed cell could be classed as simplis ic and
inexac . Mic oscopic obse a ion o umo s e eals a mul icellula 3-dimensional complex issue
unde lying de elopmen al al e a ions and a a iable deg ee o mo phological, immunopheno ypic, and
genomic he e ogenei y. Indeed, he s a egy used un il ecen ly o a ge ing one gene/p o ein/p ocess
a a ime has p o ed unsuccess ul. The Cance Genome A las (TCGA), a public epe oi e o
genomic, epigenomic, ansc ip omic and p o eomic da a, a ailable o anyone in he esea ch
communi y, ha leads o imp o emen s in he abili y o diagnose, ea and p e en cance , ep esen s
a ema kable ea [
2
]; howe e , e e y umo shows se e al mu a ions in he genome, and wi h cu en
knowledge, he sea ch o d ug candida es o each mu a ion seems un easible. Indeed, e en he
mos clinically-p omising d ugs, such as y osine kinase inhibi o s, ep esen a small ad ancemen in
compa ison o he di e si y o p ocesses and pa hway in e ac ions egula ed by hese enzymes [
3
].
The majo i y o b eas , colon, and panc ea ic cance s encompass be ween 50 and 80 mu a ed genes [
2
]
and housands o mu a ions in single cance cells; in addi ion, his single umo migh exhibi a
ema kable deg ee o mo phological and gene ic he e ogenei y a di e en s ages o i s de elopmen .
The umo mic oen i onmen (TME), which su ounds and in e ac s wi h umo cells including
he ex acellula ma ix (ECM) elemen s, s omal cells, blood and lymph essels, ne e ibe s and he
signaling molecules, has been pu o wa d o p o ide a mo e complex o e iew o how cance s de elop
and p og ess [
4
,
5
]. Resea che s, oncologis s, and pa hologis s mus unde s and ha he complexi y
and he e ogenei y ound a a cellula and molecula le el a e in luenced by a p o- umo igenic TME
and sys emic mac oen i onmen and ice e sa. Thus, in his e iew, we discuss ecen de elopmen s
in cance and i s ecosys em bioma ke s and echnologies based on an ad anced unde s anding o
he pa hophysiological na u e o cance and i s en i onmen . We analyze he TME as he modula o
o he dynamic ecosys em and examine he in insic and ex insic sys ems capable o inducing
TME ep og amming.
2. Is he TME Po en ially Rep og ammable?
The concep o cance as a disease based on issues and no only on gene ic al e a ions a he
cellula le el [
6
] opens he doo o a new unde s anding o cance and i s ea men . G owing e idence
shows ha he s oma is decisi ely in ol ed in ca cinogenesis [
7
]. An eme ging s a egy o cance
ea men is o e e he malignan pheno ype by a ge ing he TME ins ead o o addi ionally o he
cance cell popula ion [
8
], o modi y he ela ionship be ween he cells and he s omal compa men o
ob ain a esponse on he subs a e whe e umo s g ow. B eas ca cinoma cells injec ed in o he adipose
issue o syngeneic a s no exposed o he ca cinogen, e e se hei malignan pheno ype and acqui e
benign ea u es [
9
]. In addi ion, componen s o he ECM such as ype I collagen, basemen memb ane
componen s, and he p esence o no mal ib oblas s show he abili y o e e se he umo pheno ype
h ough in e ac ions wi h a a o able TME [
10
]. These obse a ions p esen cance as a unc ional
issue wi h he capaci y o espond o di e en local and dis an non-cy o oxic ac o s, ho monal,
immunological, mechanical, and o he in luences, capable o ep og amming hei s oma and cells.
3. Eme ging Sys ems o TME Rep og amming
Se e al local ac o s ha shape he immune esponse, he ECM, and he adap i e p ocess
o angiogenesis con ibu e o he TME and umo e olu ion. Hos ac o s such as in es inal
dysbiosis, neu o ansmi e s/neu oho mones implica ed in s ess esponse, hos and umo me abolism,
in ec ions, su gical and physico-chemical s imuli can also impac on ea men esponse, ac i a e he
hypo halamic–pi ui a y–ad enal (HPA) axis and inc ease he isk o me as asis [11,12].
Tumo s cells become agg essi e h ough di e en mechanisms, such as epi helial-mesenchymal
ansi ion (EMT), which p o ides cance cells wi h in asion and mo ili y p ope ies. This sugges s he
Cance s 2020,12, 1677 3 o 24
u ili y o modula ing EMT and he in e se p ocess, he mesenchymal o epi helial ansi ion (MET), a a
clinical le el [
13
] o e e he malignan pheno ype. In ac , his epo ed EMT-MET cycle implies ha
changes in cell plas ici y du ing umo p og ession a e empo a y and could be e e sed [
14
]. EMT-MET
can lead o he acquisi ion o s em cell-like ea u es, o modi y physico-chemical immuno egula o y
p ope ies and gene ic, epigene ic, and unc ional beha io a all le els [
15
]. EMT is cha ac e ized by
emodeling o he ECM and ac o s sec e ed by he mesenchymal s em cells ha ac i ely modula e
se e al oncogenic signaling pa hways such as JAK/STAT, Hedgehog, Wn , No ch, NF-
κβ
among
o he s, o help s em cells main ain hei p ope ies [16]. MET induces eg ow h and e-es ablishmen
o cance cells a seconda y/me as a ic si es. TME ac o s like Runx2 exp ession, loss o p omo e
me hyla ion, and/o miRNAs, can con ibu e o MET a he me as a ic si e [16].
Analysis and insigh in o hese p ocesses could suppo s a i ying umo al he e ogenei y a he
mo phological, immunopheno ypic, and gene ic le el h oughou he s oma hus allowing us o
iden i y a ge able ea u es [
17
]. Beyond he dynamic and p og essi e gene ic al e a ions o cance
cells, o he ac o s show mul iple connec ions on he umo al issue wi h unc ional esponse capaci ies,
such as TME molecules, ho mones, cy okines, and neu o ansmi e s, as well as he mac oen i onmen ,
whe e he in es inal mic obio a and ex e nal ac o s anging om s ess o medica ion in ake play
a ole.
3.1. In insic Sys ems Capable o Inducing TME Rep og amming
3.1.1. Remodeling TME o Enhance An i umo Immune Ac i i y
The immunological landscape o he TME plays a pi o al ole in umo p og ession. Cance
immuno he apy has gained g owing impo ance in he las decade and se e al he apeu ic s a egies
a e based on he eac i a ion o he immune sys em. Howe e , mos immuno he apies employed
o da e a e adminis e ed sys emically, leading o oxici y [
18
]. Ta ge ing he TME by in a umo al
injec ion o immunomodula o s has been s udied widely as a me hod o o e come his limi a ion, as
ha e combina o ial s a egies, s imula o y cy okines adminis a ion, inhibi o y cy okine blockade and
inhibi ion o immune checkpoin s o es o e immunological capabili y a he umo si e [
19
]. Al hough
immune checkpoin blockade (ICB) appea s e y e ec i e in a subse o pa ien s, non- esponde s
s ill emain e y high. Se e al mechanisms o ICB esis ance ha e been p oposed [
20
] bu a deepe
unde s anding o he immune landscape a he TME is equi ed o be e pa ien s a i ica ion so
hey can bene i om ICB he apy. Cha ac e iza ion o he immune cell subpopula ions is cu en ly
assessed using me hods such as luo escence-ac i a ed cell so ing (FACS) o immunohis ochemis y
(IHC)-s aining. No el ansc ip ome-based cell- ype quan i ica ion algo i hms a e being op imized
o p o ide cell- ype signa u es o immuno-oncology [
21
]. Howe e , inc easing he spa io- empo al
esolu ion o hese echniques is s ill necessa y o achie e a mo e comp ehensi e iew o he immune
TME milieu, p edic esponse o ICB and encou age he disco e y o new immuno he apeu ics [22].
The ecip ocal in e ac ion be ween cance cells and TME de e mines he ec ui men , ac i a ion,
and ep og amming o s omal, in lamma o y, and immune cells [
23
] (Figu e 1). We ha e ound
eme ging e idence o he ole o ECM emodeling, s uc u al plas ici y, and mechanical o ces in
egula ing immune cell a icking, ac i a ion, and immunological synapse o ma ion [24].
Cance cells can down egula e he exp ession o endo helial adhesion molecules sec e ed in o he
TME and equi ed o he ansendo helial mig a ion o leucocy es o diminish exposu e o cy o oxic
e ec o cells and e ade he immunological esponse [
25
]. In addi ion, ac i a ion and p oli e a ion o
leucocy es ha e been shown o be a mechanosensi i e p ocess elying on subs a e s i ness [
26
–
28
].
Leucocy es a e also able o exe a ce ain deg ee o mechanical o ce on he ECM and su ace o
in e ac ing cells [29].
Se e al componen s o he TME ha e been shown o play a di ec ole in shaping he immune
esponse. Cance -associa ed ib oblas (CAF)-media ed ECM emodeling and ib osis con ibu e
owa ds an immunosupp essed and p o- umo igenic TME by a ec ing he ec ui men and unc ion
Cance s 2020,12, 1677 4 o 24
o a ious inna e and adap i e immune cells [
30
]. A dense a chi ec u e ba ie can be imposed
by ECM elemen s such as collagen, hyalu onic acid (HA), and laminins. Whe eas high molecula
weigh HA p o ides s uc u al in eg i y and inc eases egula o y T (T egs) cell ac i i y o supp ess he
immune sys em [
31
,
32
], laminins p e en ansmig a ion and pola ize leucocy es [
33
]. In addi ion,
ECM emodeling enzymes such as me allop o einases and ma ikines di ec pola iza ion and
ac i a ion o immune cells, ac ing as cy okines and chemokines p omo ing IL exp ession and T
cell chemoa ac an [34–36].
Cance s 2020, 12, x 4 o 24
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ECM elemen s such as collagen, hyalu onic acid (HA), and laminins. Whe eas high molecula weigh
HA p o ides s uc u al in eg i y and inc eases egula o y T (T egs) cell ac i i y o supp ess he
immune sys em [31,32], laminins p e en ansmig a ion and pola ize leucocy es [33]. In addi ion,
ECM emodeling enzymes such as me allop o einases and ma ikines di ec pola iza ion and
ac i a ion o immune cells, ac ing as cy okines and chemokines p omo ing IL exp ession and T cell
chemoa ac an [34–36].
Figu e 1. Hodgkin lymphoma is a clea example o a neoplasm whe e he componen s o he TME
la gely exceed he numbe o umo cells. The di e en ial s aining o he his ological sec ions
co esponds o he same ield o he umo , showing o e lapping laye s ha e eal a he e ogeneous
composi ion o he TME. (a) H&E s aining o Hodgkin lymphoma. (b) li le p opo ion o CD30
posi i e lymphoma umo al cells. (c) Masson’s ich ome s ain o abundan ype I collagen (blue) and
(d) ep esen a ion o he hos inna e immune esponse ia mac ophage in il a e (CD68) and he
adap i e cellula esponse media ed by T cells (CD3) and B cells sec e ing an ibodies agains he
umo (CD138). Among o he s, his example cons i u es he complex immune and s omal esponse
ha de e mines he his ology, esponse o ea men , and umo p ognosis.
Gi en hese indings, we sugges adding a sys ema ic s udy o he ela ionship be ween ECM
emodeling and he in lamed s omal componen s o he TME o he cu en cha ac e iza ion o he
immune TME. In an a emp o me hodize e alua ion o he hos immune esponse in ega ding he
TME, he Immunosco e assay quan i ies immune cell densi y o p edic pa ien p ognosis and sugges
clinical ea men [37]. This akes in o accoun umo al/TME he e ogenei y and om a spa ial poin
o iew conside s he co e o he umo and i s in asi e ma gin, wi h he con ibu ion o T-cell
subpopula ions (CD3, CD8, and CD45RO); his could be included in he ana omopa hological epo
Figu e 1.
Hodgkin lymphoma is a clea example o a neoplasm whe e he componen s o he TME la gely
exceed he numbe o umo cells. The di e en ial s aining o he his ological sec ions co esponds o
he same ield o he umo , showing o e lapping laye s ha e eal a he e ogeneous composi ion o
he TME. (
a
) H&E s aining o Hodgkin lymphoma. (
b
) li le p opo ion o CD30 posi i e lymphoma
umo al cells. (
c
) Masson’s ich ome s ain o abundan ype I collagen (blue) and (
d
) ep esen a ion o
he hos inna e immune esponse ia mac ophage in il a e (CD68) and he adap i e cellula esponse
media ed by T cells (CD3) and B cells sec e ing an ibodies agains he umo (CD138). Among o he s,
his example cons i u es he complex immune and s omal esponse ha de e mines he his ology,
esponse o ea men , and umo p ognosis.
Gi en hese indings, we sugges adding a sys ema ic s udy o he ela ionship be ween ECM
emodeling and he in lamed s omal componen s o he TME o he cu en cha ac e iza ion o he
immune TME. In an a emp o me hodize e alua ion o he hos immune esponse in ega ding
he TME, he Immunosco e assay quan i ies immune cell densi y o p edic pa ien p ognosis and
Cance s 2020,12, 1677 5 o 24
sugges clinical ea men [
37
]. This akes in o accoun umo al/TME he e ogenei y and om a spa ial
poin o iew conside s he co e o he umo and i s in asi e ma gin, wi h he con ibu ion o T-cell
subpopula ions (CD3, CD8, and CD45RO); his could be included in he ana omopa hological epo
as a classi ica ion in i e le els (0–4), gi ing mo e in o ma ion ega ding he ea men op ions o
decision making in a pe sonalized medicine app oach [
38
]. P oduc ion o IFN-
γ
induces PD-L1
(p og ammed dea h-ligand 1, also e med B7–H1) umo al exp ession co ela ing wi h he p esence
o umo -in il a ing lymphocy es (TIL), which in u n p oduce IFN-
γ
(Figu e 2a). The p esence o
absence o PD-L1 and TIL de e mines he classi ica ion in o 4 sub ypes lis ed as TIME (Tumo Immune
Mic oEn i onmen ): T1 (PD-L1
−
, TIL
−
), T2 (PD-L1+, TIL+), T3 (PD-L1
−
, TIL+) and T4 (PD-L1+, TI
−
)
(Figu e 2(b1–b4)) al hough he exis ence o he la e is unde deba e because, in he absence o TIL,
PD-L1 is no expec ed [
39
]. T2 umo s ha e been shown o co ela e wi h be e esponse o an i-PD-1
he apy [
40
]. Al hough T3 umo s ha e TIL, hey do no exp ess PD-L1, mos likely due o a cellula
dys unc ion whe e T e ec o cells a e no able o p oduce IFN-
γ
[
41
]. Co-s imula ion o T3 umo s
wi h OX-40 o 4-1BB agonis s could dis up he T-cell ole ance [
42
] and ep og am he TME in o
a mo e ea able umo . Howe e , he majo i y o umo s a e classi ied as T1 and T4, bo h lacking
TILs possibly owing o an ac i e supp ession o in lamma o y in il a ion o ailu e o umo an igen
p esen a ion. The TIME ha shows abundan immune cells in he pe iphe y, bu is emp y o cy o oxic
lymphocy es (CTL) in he umo co e, is called TIME in il a ed-excluded (I-E). I possesses a high
numbe o CTLs wi h low exp ession o ac i a ion ma ke s and low CTL in il a ion in he umo
co e, meaning ha adap i e immuni y is unable o ecognize malignan cells. On he o he hand,
in il a ed-in lamed (I-I) TIME is cha ac e ized by abundan CTLs ha exp ess p og ammed cell dea h
p o ein 1 (PD-1) wi h an an i umo al cy o oxic capaci y, he e o e conside ed highly immunogenic
umo s. Se e al s a egies could induce he TME ep og amming by p omo ing an in lamma o y
in il a ion, om ocal adia ion, locally adminis e ed oncoly ic i uses, and c yo he apy o he use
o an i-cy o oxic T-lymphocy e-associa ed p o ein–4 an ibody, cance accines, and adop i e T-cell
he apy. Cos imula o y a ge ing o 4-1BB o OX40 could also po en ially inc ease umo in il a ion in
T1 and T4 umo s [
42
,
43
]. A pan-cance combined quan i a i e analysis o genomics and p o eomics o
he umo ma isome (ECM and i s ela ed componen s) no only ela es he umo ma isome index o
mu a ional load and umo pa hology bu also p edic s su i al a es. Wo hy o no e, high umo
ma isome index umo s e ealed en ichmen o speci ic umo -in il a ing immune cell popula ions,
along wi h signa u es p edic i e o esis ance o ICB, and clinically a ge able immune checkpoin s [
44
].
3.1.2. The Ne ous Sys em (NS), Ad enaline and Glucoco icoids, and Thei Role in Me as ases
In cance bo h he p o ec i e mechanisms o he immune sys em and he p o ec i e in luence o
he NS a e los [
45
], lea ing he pe iphe al ne ous sys em (PNS) as a c i ical pa o he umo s oma,
i s unc ion, and i s s uc u e [
46
]. While he e is inc eased insigh in o he unc ion and signi icance
o ne ous componen s o TME, he neu obiology o cance is an eme ging discipline in oncology. I
p o ides g owing e idence on he mas e egula o y e ec on immuni y o neu o ansmi e s and
psychosocial ac o s [
47
] and shows ha umo s a e no isola ed s uc u es, bu in e ac wi h di e en
sys ems, di ec ly cell o cell, h ough elec omagne ic signals, as well as h ough neu onal signaling
molecules [48].
TME componen s such as ne e ibe s a e impo an issue elemen s in de ining he in a- and
pe i umo al neu al milieu [
49
–
51
]. Clinical and
in i o
expe imen s ha e shown ha umo inne a ion
elease neu o ansmi e s, neu opep ides, and neu o ophins, ac ing di ec ly on ecep o s exp essed by
cance cells and modula ing signaling, apop osis, angiogenesis, me as ases, and p og ession [
52
,
53
]. In
ac , in gas ic cance pa ien s, umo s age has been co ela ed wi h neu al densi y whe eas ago omy
educed he isk o gas ic cance [
54
]. The umo cells emi humo al and ne ous signals ha no only
each he b ain, which uses he in o ma ion o modula e he neu oendoc ine and immune sys em [
55
]
bu can sp ead ia pe ineu al in asion o su ounding ne es and ela ed s uc u es. No ably, pe ineu al

Cance s 2020,12, 1677 6 o 24
in asion ela es o poo p ognosis, co ela ing wi h dec eased o e all and disease- ee su i al ime in
colon, panc ea ic, gas ic, and head and neck ca cinoma [56–59].
Cance s 2020, 12, x 6 o 24
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Figu e 2. Schema ic ep esen a ion o TIME (Tumo Immune Mic oEn i onmen ) classi ica ion. (a)
The PD-1/PD-L1 pa hway ep esen s an adap i e immune esis ance mechanism exe ed by umo
cells in esponse o endogenous immune an i- umo ac i i y. Engagemen o PD-L1 exp essed on he
umo cells o PD-1 ecep o s on he ac i a ed T cells leads o inhibi ion o cy o oxic T cells. (b1–b4)
Classi ica ion in o 4 sub ypes lis ed as TIME. (b1) PD-L1₋, TIL⁻ is classi ied in o ype 1 (T1). (b2) PD-
L1+, TIL+, belongs o ype 2 (T2). (b3) PD-L1−, TIL+ belongs o ype 3 (T3) and (b4) PD-L1+, TIL−,
classi ied as ype 4 (T4) al hough i s exis ence is unde deba e. MHC: majo his ocompa ibili y
complex. TCR: T cell ecep o . TAAs: umo -associa ed an igens. TSAs: umo -speci ic an igens.
Legends a he op igh .
Mos human umo s exp ess su ace ad ene gic ecep o s, which when ac i a ed by s ess
ca echolamines play a ole in acili a ing umo igenesis and umo p og ession [60]. In lung and
b eas in i o cance models, s imula ion o β-ad ene gic ecep o s esul ed in he inc eased
me as a ic po en ial o cance cells, among o he s ia na u al kille (NK)-cell, mac ophage signaling,
o os eoblas s imula ion [61]. In i o, in i o, and clinical s udies show ha s ess- ela ed p ocesses
can a ec he pa hways in ol ed in cance p og ession, including immune egula ion, angiogenesis,
and in asion. I has been shown ha ch onic use o be a-blocking d ugs (an agonizing
no epineph ine and ad enaline (Table 1), is associa ed wi h lowe ecu ence and mo ali y o b eas
cance and malignan melanoma and could o dec ease p os a e cance isk [62]. Mo eo e , low-dose
glucoco icoids can supp ess o a ian cance p og ession and me as asis, p obably h ough
up egula ion o me as asis supp esso mic oRNAs, bu also ia modula ion o umo -associa ed
mac ophages and myeloid-de i ed supp esso cells (MDSCs) in he TME [63]. In addi ion, he
sympa he ic ne ous sys em (SNS) egula es pa hological gene exp ession in human umo s, leading
o DNA damage epai inhibi ion, oncogene ac i a ion, apop osis, and anoikis supp ession [64].
Figu e 2.
Schema ic ep esen a ion o TIME (Tumo Immune Mic oEn i onmen ) classi ica ion.
(
a
) The PD-1/PD-L1 pa hway ep esen s an adap i e immune esis ance mechanism exe ed by umo
cells in esponse o endogenous immune an i- umo ac i i y. Engagemen o PD-L1 exp essed on he
umo cells o PD-1 ecep o s on he ac i a ed T cells leads o inhibi ion o cy o oxic T cells. (
b1
–
b4
)
Classi ica ion in o 4 sub ypes lis ed as TIME. (
b1
) PD-L1-, TIL
−
is classi ied in o ype 1 (T1). (
b2
) PD-L1+,
TIL+, belongs o ype 2 (T2). (
b3
) PD-L1
−
, TIL+belongs o ype 3 (T3) and (
b4
) PD-L1+, TIL
−
, classi ied
as ype 4 (T4) al hough i s exis ence is unde deba e. MHC: majo his ocompa ibili y complex. TCR:
T cell ecep o . TAAs: umo -associa ed an igens. TSAs: umo -speci ic an igens. Legends a he
op igh .
Mos human umo s exp ess su ace ad ene gic ecep o s, which when ac i a ed by s ess
ca echolamines play a ole in acili a ing umo igenesis and umo p og ession [
60
]. In lung and
b eas
in i o
cance models, s imula ion o
β
-ad ene gic ecep o s esul ed in he inc eased me as a ic
po en ial o cance cells, among o he s ia na u al kille (NK)-cell, mac ophage signaling, o os eoblas
s imula ion [
61
].
In i o
,
in i o
, and clinical s udies show ha s ess- ela ed p ocesses can a ec he
pa hways in ol ed in cance p og ession, including immune egula ion, angiogenesis, and in asion. I
has been shown ha ch onic use o be a-blocking d ugs (an agonizing no epineph ine and ad enaline
(Table 1), is associa ed wi h lowe ecu ence and mo ali y o b eas cance and malignan melanoma
and could o dec ease p os a e cance isk [
62
]. Mo eo e , low-dose glucoco icoids can supp ess
Cance s 2020,12, 1677 7 o 24
o a ian cance p og ession and me as asis, p obably h ough up egula ion o me as asis supp esso
mic oRNAs, bu also ia modula ion o umo -associa ed mac ophages and myeloid-de i ed supp esso
cells (MDSCs) in he TME [
63
]. In addi ion, he sympa he ic ne ous sys em (SNS) egula es pa hological
gene exp ession in human umo s, leading o DNA damage epai inhibi ion, oncogene ac i a ion,
apop osis, and anoikis supp ession [
64
]. O he neu o ansmi e s such as endo phins in luence umo
p oli e a ion and elec ical s imula ion o he hypo halamus, inc easing he cy o oxici y o NK cells,
while pinealec omy a ec s he cou se o b eas cance , an e ec e e sed by he adminis a ion o
mela onin [48].
Unde s anding he in e ac ion be ween cance cells and NS is becoming indispensable o he
de elopmen o new a ge ed he apeu ic in e en ion.
3.1.3. In es inal Mic obio a as TME Regula o
In cance , he in es inal mic obio a (IMB), he complex and dynamic popula ion o mic oo ganisms
ha li e in he diges i e ac s, is o wo- old impo ance: on he one hand, o i s e iopa hogenic
ole [
65
] and on he o he o i s e ec on cance ea men e icacy, bo h h ough an impac on TME [
66
].
Se e al s udies link he IMB o he ma u a ion o he immune sys em, he s uc u e o he TME,
me abolism modula ion, esponse o chemical and immuno he apeu ic ea men , and mos hallma ks
o cance [
66
–
69
]. The exis ence o a umo mic obio a, ound in si u in he TME, could, he e o e,
ha e majo physiopa hological and he apeu ic implica ions [
70
,
71
]. All hese unc ions pe haps pa ly
owing o he p i ileged bidi ec ional communica ion be ween IMB and NS, h ough he so-called
neu en e ic axis, HPA egula o , and he accompanying homeos a ic equilib ium iangle made up by
he endoc ine, immune and NS [72].
Impo an ly, IMB modula es he immuno he apeu ic esponse o an i-PD-1 in pa ien s wi h
melanoma [
73
] and epi helial umo s [
74
], showing how IMB egula ion is a key ac o in he equilib ium
be ween T eg cells, an igen p ocessing/immunoglobulin-sec e ing cells and he TME s uc u e [
75
].
On he o he hand, dysbiosis de elops a p o-in lamma o y en i onmen , de egula es he immune
esponse, and diminishes he concen a ion o chemo he apeu ic agen s by inc easing desmoplasia
in he TME [
75
]. Me agenomic analyses ha e shown an en ichmen o Fusobac e ium nuclea um in
colo ec al ca cinoma issue (Table 1). Fusobac e ium nuclea um causes immunosupp ession and ec ui s
umo -in il a ing immune cells, hus yielding a p o-in lamma o y mic oen i onmen , which p omo es
colo ec al neoplasia p og ession [
76
]. An ibio ics ad e sely a ec o e all and disease- ee su i al in
cance , ega dless o o he c i e ia, due o he des uc ion o IMB [
74
], equi ed o chemo he apy o
be e ec i e. O e all su i al o 20 mon hs wi hou and 11 mon hs wi h an ibio ics (15 and 8 mon hs
espec i ely in lung cance ) show how he IBM go e ns immune checkpoin s and opens up new
app oaches o a decisi e in es inal ecosys em in esis ance o inhibi o s o immune esponse con ol
and modi ica ion o TME [77].
This opens a new ield o esea ch and clinical applica ion and pu s o wa d he IMB as an
in e es ing bioma ke ha de e mines he e icacy o immuno he apy ea men [78] (Table 1).
Cance s 2020,12, 1677 8 o 24
Table 1. E alua ion me hods o eme ging bioma ke s.
E alua ion G oups Pa ame e s Indica o s De ec ion Me hod Re e ences
TME In lamma o y in il a ed cells TAM CD68, CD163 IHC [79]
TAN CD15, CD32, CD35 [80]
T helpe CD4 [81]
Cy o oxic T cells CD8 [82]
Memo y T cells CD8, CD4, CTLA-4 [83]
T egs FOXP3, CD4, CD25 [84]
DC CD141, CLEC9, CD11c [85,86]
NK CD16, CD56, PD-L1, PD-L2 [87]
B lymphocy es CD20 [88]
S omal cells CAF αSAM, CD10, FSP1, AEBP1 [89,90]
Schwann cells S100, GFAP, p75NTR [91]
MSC SC Sox2, Oc 4, CD133, Nes in, c-ki [92]
Fibe s Collagen ype I T. Masson, an Gieson HC [93,94]
Collagen ype III [94]
Elas ic ibe s O cein, Gomo i, Snook, Wilde , Ve hoe [94]
In e s i ial luid P o eoglycans Alcian blue [95]
Fib onec in An i ib onec in IHC [96]
Laminin An ilaminin [97]
Vi onec in An i i onec in [98]
G ow h ac o TGF-βAS [99]
Cy okines Lymphokines ELISA [100]
P o eases Me allop o einases [100]
Oxygen (ROS) GSH/GSSG [100]
3D s uc u e Fib es and Cellula elemen s Topology G aph heo y [101,102]
Mechanical o ces Focal adhesions (F-ac in, myosin II, α-ac in, ascin) IF [103]
S ess ib es [103]
Mechano ansduc ion Mechano-ac ua ed shu ling p o eins (β-ca enin, zyxin) [103]
LINC complex (SUN and nesp ins) [103]
Sys emic ac o s Glycolic index ↑me abolic index 18FDG PET [104]
pH Acidosis Elec oly es se um concen a ion Enzyma ic [105]
Oxygen sa u a ion Hypoxia ↑HIF-1, ↑lac a e IHC [106]
Me abolism In lamma o y esponse ↓VEGF AS, ELISA [107]
In es inal mic obio a Dysbiosis ↑Bac e oids MALDI-TOF MS [76,108–110]
↑Fusobac e ium NGS [76,108–110]
↑Po phy omonas 16S RNA [76,108–110]
↑En e obac e [76,108–110]
↑Cyb obac e [76,108–110]
Ne ous sys em De egula ion ↑No epineph ine, HPLC [62]
↑Dopamine [111]
↑subs ance P [112]
↓β-endo phins [113]
AS: abso p ion spec ome y; DC: dend i ic cells; CAF: cance -associa ed ib oblas s; 18FDG: luo odeoxyglucose; GSH: glu a hione; GSSG: glu a hione disul ide; HC: his ochemis y;
HPLC: high-pe o mance liquid ch oma og aphy; IF: immuno luo escence; IHC: immunohis ochemis y; LINC: linke o nucleoskele on and cy oskele on; MALDI-TOF MS: ma ix-assis ed
lase deso p ion/ioniza ion ime-o - ligh mass spec ome y; MSC: mesenchymal s em cells; NGS: nex -gene a ion sequencing; NK: na u al kille cells; PET: posi on emission omog aphy;
ROS: eac i e oxygen species; 16S RNA: ibosomal RNA 16S; SC: s em cells; TAM: umo -associa ed mac ophage; TAN: umo -associa ed neu ophils; TME: umo mic oen i onmen ;
T egs: egula o y T cells. Adap ed om Nogue a e a ., 2019 [46].
Cance s 2020,12, 1677 9 o 24
3.1.4. Me abolic Regula ion and Mi ochond ial Dys unc ion o Cance
O o Wa bu g pionee ed he s udy o umo me abolism [
114
], which es ablished hypoxia and
acidosis as cha ac e is ics o cance . This speci ic me abolic pa e n is based on ae obic glycolysis o
umo cells (Wa bu g e ec ), which is a necessa y sou ce o subs a es o uncon olled umo cell
g ow h conside ing ha umo supp esso oncogenes and genes migh be ca ie s o bioene ge ic
al e a ions [
115
]. Me abolic ep og amming is an essen ial mechanism by which cance cells swi ch
o di e en pa hways o ob ain he ene gy necessa y o su i e and p oli e a e. This me abolic and
bioene ge ic shi sus ains high p oli e a ion a es, as ca bon sou ces a e apidly di e ed o p oduce
lipids, nucleic acids, and p o eins [
116
]. This p ocess is also essen ial o egula e he in e ac ion
be ween cance and immune cells, as well as o ec ui a a ie y o immune cells [
117
]. Cance
me abolism has led o a scien i ic ocus on umo cell ep og amming o glucose consump ion [
118
]
o co ec he dys unc ional beha io o umo s. Indeed, i is well accep ed ha abe an cance
me abolism is linked o ea men esis ance [
119
]. Glu amine le els, which a e dec eased in he
hypoxic co e o he umo , d i e his one me hyla ion, and umo de-di e en ia ion o lead d ug
esis ance [
120
]. Glu amine also a ec s he s oma by changing i o a umo -p omo ing en i onmen
h ough inc eased glu amine-induced au ophagy in ib oblas s [
121
]. Lipid me abolism also suppo s
TME ep og amming; indeed, i has been ound ha T egs accumula e lipids and combine glycolysis
and a y acid syn hesis and oxida ion o su i e [
122
]. In addi ion, ecen s udies show ha he
me abolic s a e o TME, oxygen le els, acidi y, and nu ien a ailabili y a ec T-cell in il a ion, su i al,
and e ec o unc ion [
123
,
124
]. Fu he mo e, g adien s o ex acellula me aboli es, le els o ischemia,
hypoxia, and lac a e ac as mo phogens and inc ease s omal s i ness. Among o he indings, me abolic
al e a ions o he s oma impac umo he e ogenei y, a ec ing bo h mo pho-immunopheno ypic and
gene ic ea u es [
17
]; hey con ibu e o iden i ying sampling e o as a cause o lack o co ela ion
be ween bioma ke esea ch and esponse o immuno he apeu ic ea men ; shed ligh on he spa ial
s uc u e o he TME depending on he Wa bu g e ec [
125
] and inally show he abili y o umo cells
o ep og am hei me abolism and su i e he ha sh condi ions o TME [126].
Fu he mo e, mi ochond ial lesions no only a ec umo me abolism bu also al e apop osis
and p esen cance as mi ochond ial dys unc ion [
127
]. The cells ac as i he e is oxygen sho age,
e en i he e is abundance as HIF-1a main ains he exp ession o no mally inac i e genes ha make
he cell immo al, unable o ac i a e p og ammed cell dea h and keep i s ep oduc ion p og am
ac i a ed [
128
] (Table 1) h ough he conca ena ion o hypoxia, lac a e le els, malignancy, and
me as a ic capaci y. While he highly glycoly ic umo cell is e y agg essi e and in asi e, cells wi hou
mi ochond ial DNA canno o m umo s [
129
], unless hey acqui e i om adjacen cells, as occu s
h ough mi ochond ia dona ion om s omal cells o umo -de icien umo cells. Tumo cells eco e
espi a o y capaci y and biological agg essi eness when hey ake up mi ochond ial DNA om TME
cells [
130
]. A p omising pe spec i e could be based a ound he abili y o he mi ochond ia o supp ess
he malignan pheno ype [127].
3.1.5. Mechano ansduc ion and Bio enseg i y as P ope ies o he TME
The mechanical p ope ies o he umo s oma a e de e minan s o cell biology and clinical
beha io [131]. A ecu en umo ea u e is he s i ness o he s oma, h ough which umo s can be
de ec ed by palpa ion o adiological examina ion. The main mechanical pe u ba ions o he TME a e
s i ness o he ECM, ele a ed in e s i ial luid p essu e, and/o an inc ease in solid ension caused by
umo g ow h [
132
]. These mechanical p ope ies a e di icul o s udy and e alua e wi h con en ional
his ological echniques, and ad ances in he ield now s em om a new knowledge a ea called
mechanobiology, an in e disciplina y science b anch combining biology, physics and enginee ing.
The umo issue bio enseg i y mechanism is based on ension o ces on cells and a ious
elemen s o he ECM, which ecei e mechanical impac h ough speci ically designed elemen s [
102
].
The physical s imuli a he issue, cellula and molecula le el p o oundly a ec he chemical signals o
he umo cell, capable o pe cei ing he mechanics o he subs a e and ans e ing his in o ma ion
Cance s 2020,12, 1677 16 o 24
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