Senescent Remodeling of the Innate and Adaptive Immune System in the Elderly Men with ...

12 Pages·2015·1.36 MB·English

Hindawi Publishing Corporation
Current Gerontology and Geriatrics Research
Volume 2014, Article ID 478126, 11 pages
http://dx.doi.org/10.1155/2014/478126
Review Article
Senescent Remodeling of the Innate and Adaptive Immune
System in the Elderly Men with Prostate Cancer
GianluigiTaverna,1MauroSeveso,1GuidoGiusti,1RodolfoHurle,1PierpaoloGraziotti,1
SanjaŠtifter,2MaurizioChiriva-Internati,3andFabioGrizzi1
1HumanitasClinicalandResearchCenter,ViaManzoni56,Rozzano,Milan20089,Italy
2DepartmentofPathology,SchoolofMedicine,UniversityofRijeka,51000Rijeka,Croatia
3DivisionofOncologyandHematology,TexasTechUniversityHealthSciencesCenter,Lubbock,TX79409,USA
CorrespondenceshouldbeaddressedtoFabioGrizzi;[email protected]
Received31July2013;Revised26January2014;Accepted10February2014;Published19March2014
AcademicEditor:Moise´sEvandroBauer
Copyright©2014GianluigiTavernaetal. This is an open access article distributed under the Creative Commons Attribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Despiteyearsofintensiveinvestigationthathasbeenmadeinunderstandingprostatecancer,itremainsamajorcauseofdeath
inmenworldwide.Prostatecanceremergesfrommultiplealterationsthatinducechangesinexpressionpatternsofgenesand
proteinsthatfunctioninnetworkscontrollingcriticalcellularevents.Basedontheexponentialagingofthepopulationandthe
increasinglifeexpectancyinindustrializedWesterncountries,prostatecancerintheelderlymenisbecomingadiseaseofincreasing
significance.Agingisaprogressivedegenerativeprocessstrictlyintegratedwithinflammation.Severaltheorieshavebeenproposed
thatattempttodefinetheroleofchronicinflammationinagingincludingredoxstress,mitochondrialdamage,immunosenescence,
andepigeneticmodifications.Here,wereviewtheinnateandadaptiveimmunesystemsandtheirsenescentremodelinginelderly
menwithprostatecancer.
1.Introduction It has been ascertained that the human prostate is the
site of origin for the two most prevalent diseases of elderly
Prostate cancer is the most prevalent malignancy in men men:benignprostatichyperplasia(BPH)andprostatecancer
worldwideandisaleadingcauseofcancerdeath[1,2].Several [13, 14]. Prostate cancer is a highly heterogeneous disease
men with localized prostate cancer will never suffer any encompassing a wide variety of pathological entities and
symptomsoradverseeffectsofthedisease,butbecauseofthe a range of very different clinical behaviors [15]. This is
difficultiesinidentifyingthisgroupofpatientsthemajority underpinnedatmolecularlevelbyacomplexarrayofgenetic
receive radical local treatment, which can mainly result in alterations that affect cell processes, thus determining the
erectiledysfunctionandurinaryleakage[3,4].Thestillopen dynamical progression of the neoplastic disease and its
questionforcliniciansisdecidingwhichmenhave“fastgrow- variable response to treatment (Figure1) [16, 17]. Genomic
ing” cancers that need essential treatment and which men alterations with a potential involvement in prostate cancer
have“slowgrowing”cancersthatwillnevertroublethem[5]. include somatic mutations, gene deletions or amplifica-
Prognosticmarkersmayhelptoavoidunnecessarytreatment tions,andchromosomalrearrangements[17–21].Epigenetic
and identify patients with poor outcomes who would be changes, more specifically DNA methylation, are the most
candidates for trials of adjuvant treatment [6–9]. Based on common alterations in prostate cancer [22]. These changes
the exponential aging of the population and the increasing areassociatedwithtranscriptionalsilencingofgenes,leading
lifeexpectancyinindustrializedWesterncountries,prostate to an altered cellular behavior. In light of this, epigenetic
cancer in elderly men is becoming a disease of increasing markers, especially the glutathione S-transferase pi gene
significance[10–12]. (GSTP1),havebeenlargelyproposedaspotentialbiomarkers
2 CurrentGerontologyandGeriatricsResearch
Proliferative Localized
Natural Extracapsular
inflammatory HGPIN confined Metastasis
tissue invasion
atrophy cancer
t0 t1 t2 t3 tn−1 tn
Figure1:Multistateprostatecarcinogenesisdeterminedbytheprogressionofdifferentqualitativestatesidentifiableinthedevelopment
of cancer from normal tissue. The time parameter (𝑡0,𝑡1,...,𝑡𝑛−1,𝑡𝑛) depends on a large number of variables interconnected in many
waysinanonlinearmanner.Thismakesitextremelydifficulttopredicttheexacttimeintervalbetweentwosuccessivestates.Although
carcinogenesisisacontinuum,itsdifferentiationintosuccessivestatesisbasedondifferencesinhistologicalandclinicaldata.Proliferative
inflammatory atrophy (PIA) is a frequently observed lesion in prostate biopsies and some investigators have postulated its involvement
inprostatecarcinogenesis.PIAsharesgeneticalterationswithhigh-gradeprostaticintraepithelialneoplasia(HGPIN)andprostatecancer.
HGPINiscurrentlyregardedastheprecursorlesiononthebasisofpathological,epidemiological,andcytogeneticevidence.HGPINlesions
canbesubdividedintoatleastfourdifferentarchitecturalpatterns.
for the evaluation of the probability of biochemical recur- shortly after prostatectomy (<1 year) and patients that did
rence [23]. Other markers have a strong body of scientific not relapse in the first four years after prostatectomy and
data supporting their role in prostate cancer diagnosis, identified 131 differentially expressed microarray probe sets
most notably adenomatous polyposis coli (APC), retinoic between these two categories. They conclude that tumor-
acid receptor beta (RARB), RAS association domain family adjacentprostatecancerstromacontainsnumerouschanges
protein 1 (RASSF1), CDH1, CDKN2A (p16), and the O(6)- in gene expression at the time of diagnosis that correlate
methylguanine-DNA methyltransferase (MGMT) [22, 24]. with the chance of relapse following prostatectomy [42]. It
Prostate cancer clinical phenotypes range from indolent or is likely that the differences in RNA expression are often
clinicallyinsignificanttolocallyaggressiveormetastatic[25– reflected in differences in chromatin modification, DNA
27]. A high number of gene expression profiling studies methylation, and protein levels, which could also serve as
have been carried out to attempt the establishment of a stromal markers for progression [43]. Reinertsen et al. [44]
“molecular”stagingsystem,buttheidentificationofgenetic showed that prostate fibroblast primaryculturesfrom areas
markers that predict aggressive disease has not yet been withcancerandhyperplasiawithPC-3cellsseemtomakethe
clinicallydemonstrated[28–33]. cancerousandhyperplasticfibroblastsmorelikeeachother,
Molecular associations with prostate cancer phenotypes asthenumberofdifferentiallyexpressedgenesdecreases.
continue to be fragmentary and, in some cases, have been Thecellsoftheimmunesystemthatarecommonlyfound
− +
poorlysubstantiatedbyfollow-upinvestigations.Histopatho- infiltratingprostatecancerincludeIL 17 macrophages[45,
logical examination reveals that, like other solid tumors, 46],neutrophils[47],mastcells[48],naturalkillercells[49],
prostatecancerisassociatedwithdiverseimmunecellinfil- andcellsassociatedwithanadaptiveimmuneresponse,that
tratesandthat,inthecancercontext,epithelialcellscoexist is, T- and B-lymphocytes (Figure2) [50–54]. Although it is
withextracellularmatrixcomponentsandnonneoplasticcell commonly thought that an immune response localized to
types,includingfibroblastsandendothelialcells,whichcol- the tumor inhibits cancer growth, it is now clear that some
lectivelyformthetumorstroma(Figure2)[34–36]. Several types of tumor-associated inflammation may also exert an
lines of evidence support the concept that tumor stromal opposite action, at least at some point of prostate cancer
cells are not merely a scaffold, but rather they influence naturalhistory[55].Here,wereviewtheinnateandadaptive
growth, survival, and invasiveness of cancer cells, dynami- immune systems and their senescent remodeling in elderly
callycontributingtothetumormicroenvironment,together menwithprostatecancer.
with immune cells [35, 37–40]. It is known that interac-
tions between epithelium and the surrounding stroma are 2.TheProstateCancerintheElderly
required to maintain organ function and that these inter-
actions provide proliferative and migratory restraints that Prostatecancer,whichismostoftendiagnosedinmenover
define anatomical and positional information, mediated by the age of 65 years, still remains one of the most common
severalgrowthfactorsandextracellularmatrixcomponents humancancers[11].Treatmentoptionsvarydependingonthe
[41]. When cancer develops, transformed cells lose these stageandgradeofthecancer,aswellaspatientcomorbidity
constraints while stroma adapts and coevolves to support and age. More than one-half of men aged younger than
the “function” of the tumor [35]. The prostate represents 65 years are treated with radical prostatectomy [1]. Those
an example of organ that relies on its surrounding stroma aged 65 years to 74 years commonly undergo radiation
duringnormaldevelopmentandcancerprogression[35].Jia therapy (nearly, 40%). Data show similar survival rates for
et al. [42] compared Affymetrix gene expression profiles in patientswithearlystagediseasewhoaretreatedwitheither
stromaneartumorandidentifiedaset of115probesetsfor ofthesemethods.Activesurveillanceratherthanimmediate
whichtheexpressionlevelsweresignificantlycorrelatedwith treatmentisacommonlyrecommendedapproach,especially
time-to-relapse.Theauthorscomparedpatientsthatrelapsed foroldermenandthosewithlessaggressivetumorsand/or
CurrentGerontologyandGeriatricsResearch 3
Innate immune cells
Adaptive immune cells
Fibroblasts
Myofibroblasts
Natural Prostate
prostate Endothelial cells cancer
tissue
Adipocytes
Pericytes
Epithelial cells
Extracellular matrix
Cytokines-chemokines
Time (t)
Figure2:Histopathologicalexaminationrevealsthatprostatecancerisassociatedwithdiverseimmunecellinfiltratesandthat,inthecancer
context,epithelialcellscoexistwithextracellularmatrixcomponentsandnonneoplasticcelltypes,includingfibroblastsandendothelialcells,
whichcollectivelyformthetumourstroma.Evidencesupportstheconceptthattumourstromalcellsarenotmerelyascaffold,butratherthey
influencegrowth,survival,andinvasivenessofcancercells,dynamicallycontributingtothetumourmicroenvironment.Theinteractions
betweenepitheliumandthesurroundingstromaarerequiredtomaintainorganfunctionandprovideproliferativeandmigratoryrestraints
that define anatomical and positional information, mediated by several growth factors, cytokines, chemokines, and extracellular matrix
components.Whencancerdevelops,transformedcellslosetheseconstraintswhilestromaadaptsandcoevolvestosupportthe“function”of
thetumour.
moreseriouscomorbidconditions[1,56–59].Itisknownthat contributetoincreasedmorbidityandmortality.Ithasbeen
overdiagnosisandovertreatmentarefrequentintheelderly ascertained that bidirectional interrelations of both sys-
men.Competingmortalityrisksofmenolderthan75years tems are present in the young and in the elderly; that is,
maysupersedetheriskofdyingfromprostatecancerseveral endocrinosenescence modulates the immune system and
fold[10]. immunosenescence changes the endocrine system. Terms
Itisnowacceptedthatagingisassociatedwithanincrease suchasalteration,deterioration,anddeclinedonotaccount
in a wide range of age-related diseases, including cardio- for the complexity of immunosenescence [69]. Hence, the
vascular dysfunction, metabolic disorders, neurodegenera- more appropriate term of “senescent immune remodeling”
tion, and cancer [60]. Even in the absence of identifiable hasbeenproposed[70].Itisknownthatchronicinflamma-
disease, the physiology of organs, tissues, and cells declines tion might contribute to general aging in several ways. The
throughoutlife.Withinatissue,bothdifferentiatedcellsand perpetual presence of circulating proinflammatory factors
adult stem cells are susceptible to intrinsic and extrinsic maykeeptheimmunesysteminastateof“chroniclow-level
changesduringaging[61–64].Inadditiontothesedamages, activation.”Thischronicimmuneactivationmightdetermine
cellularagingisalsoinfluencedbytheexposuretoextrinsic immunosenescence, caused primarily by an exhaustion of
factors, including inflammatory cytokines [65–67]. It has the pool of na¨ıve T-cells, clonal expansion among T- and
been accepted that mammalian aging is associated with B-lymphocytes,andtheconsequentshrinkageof“immuno-
molecular, cellular, and physiological changes characterized logicalspace”;together,thesephenomenareducethebody’s
by a deteriorating homeostatic balance associated with the ability to respond to new antigens [71, 72]. In addition to
increasing prevalence of neoplasia and other chronic dis- causing immunosenescence, some proinflammatory factors
eases [68]. Although the correlation between inflammatory (i.e., matrix metalloproteinase-3 (MMP-3)) may degrade
pathwaysandagingisnowestablished,itremainsdifficultto the tissue microenvironment [73]. Several cytokines pro-
demonstrateacausalconnection[65].Severaltheorieshave ducedbysenescentcells,includinginterleukin-6(IL-6)and
beenproposedtodefinetheroleofchronicinflammationin interleukin-8(IL-8),areknownasattractorsandactivatorsof
aging.Theyincludetheredoxstress,mitochondrialdamage, innateimmunecells,whichcandestroytissueenvironments
immunosenescence, endocrinosenescence, epigenetic mod- by virtue of the oxidizing molecules they release [74]. It is
ifications, and age-related diseases. Immunosenescence, a nowascertainedthatimmunosenescenceleadstoincreased
stateofgradualdeteriorationoftheimmunesystembrought incidence of infectious diseases morbidity and mortality as
on by natural aging, is felt to be a significant contributor wellasheightenedratesofotherimmunedisorderssuchas
to this increased risk. Careful analyses of healthy people autoimmunity,cancer,andinflammatoryconditions[75].
ranginginagefromneonatestocentenarianssuggestthata Itisknownthat,afterpeakreproductiveage,thehistology
complexandcontinuousremodelingoftheimmunesystem of the prostate begins to undergo age-related changes that
occurs with age. In particular, deterioration of the immune continue throughout life. Additionally, it has been shown
systemandtheendocrinesystemduringagingisthoughtto that the size of the prostate typically increases throughout
4 CurrentGerontologyandGeriatricsResearch
a man’s lifetime and that different growth characteristics in increasedriskofaggressiveprostatecanceramongoldermen
eachprostatezonemaycontributetodifferencesintheoverall andthatappropriateclinicaltrialsarecompulsorytodefine
growthratewithage[76].Turkbeyetal.haverecentlyshown theroleoftestosteroneinthedevelopmentofprostatecancer
that magnetic resonance imaging is able to document age- and insure the safety of testosterone-replacement therapy
related changes in prostate zonal volumes [77]. Although [83].
key mechanisms are not yet completely understood, these
changesmightbeattributedtoalteredandrogenactionand
inflammatory processes that lead to either an unabated 3.TheInnateImmunityandProstateCancer
trophiceffectontheglandand/orachronicinflammation.It
ispossiblethatrepeatedepithelialinsultsustainedthrough- It has been widely demonstrated that the innate immune
out the aging process results in a change of biology from systemisthefirstlineofdefenseagainstinfections.Although
oneofdifferentiatedreproductivefunctiontooneofchronic itisgenerallyacceptedthatsomeaspectsofinnateimmunity
woundrepair.Dasetal.[78]haveinvestigatedaging-related are well preserved in aging, several lines of evidence in
changes in important cellular pathways, by systematically the last decade support the notion that immunosenescence
determiningtheeffectsofgrowthanddevelopmentandaging affectsnotonlyadaptiveimmunitybutalsoinnateimmunity.
on proteomic profiles in different lobes of the rat prostate. Aside from T- and B-lymphocytes, innate immune cells
They found that proteins modulated during growth and orchestrateaninflammatoryenvironmentthatmayfunction
developmentinthedorsolateral(DL)andventral(VL)lobes to either stimulate or inhibit cancer growth. Various innate
areinvolvedinavarietyofbiologicalprocessesincludingcell immunitycellshavebeenimplicatedinprostatecanceronset,
development,whereasproteinsmodulatedduringagingwere progression,andmetastasis.Amongthese,macrophagesare
predominantlyrelatedtoantioxidantactivityandimmunity a primary source of secreted proinflammatory cytokines
[78].Interestingly,theimportanceoftheGolgiapparatusin and are generally distinguished as type 1 (M1) or type
cellular activities as a stress sensor, apoptosis trigger, lipid/ 2 (M2) [84, 85]. M1s generally have an interleukin (IL)
protein modifier, mitotic checkpoint, and a mediator of 12lowIL-10highphenotype,showimpairedexpressionofreac-
prostatemalignanttransformationhasbeenhighlighted[79]. tive nitrogen intermediates and poor antigen presentation,
Richieetal.[80]comparedthelevelsofselenium,glutathione, andhavetumoricidalcapacity,whiletheyshowhighexpres-
andprotein-boundglutathione(GSSP)inbloodandprostate sion of angiogenic factors (including vascular-endothelial
tissues in young (4 months), mature (12 months), old (18 growthfactor(VEGF),epidermal-growthfactor(EGF),and
months), and very old (24 months) male F344 rats. They semaphorin 4D), MMPs, and cathepsins as well as of the
found that, after 12 months, an 85% reduction in selenium growth arrest-specific protein GAS6 [86–88]. Additionally,
in the DL was observed, while levels in other lobes were M1 can support T-helper 1 (Th1) adaptive immunity [89].
unchanged.Inanimalsofallages,levelsofglutathionewere Conversely, M2s secrete immunosuppressive cytokines and
thelowestintheVLthanintheDLandnosignificantchanges promote tumor growth [90]. It has been shown that cancer
wereobservedinglutathionelevelsby18months.However, cells shape their interaction with macrophages by escaping
GSSP,amarkerofoxidativestress,wasincreased90%after18 phagocytosis and by promoting an M2-like polarization
monthsintheDLonly.Thesefindingsofage-relatedchanges throughout chemokines and polarizing cytokines including
inGSSPandseleniumintheDLprostateareconsistentwith chemokine ligand 2 (CCL2), colony stimulating factor 1
the sensitivity of this lobe to carcinogenesis and, thus, may (CSF1), macrophage slowing factor (MSF), tumor necrosis
be playing a mechanistic role. It is known that androgens factor-alpha(TNF-𝛼),IL-10,andtransforminggrowthfactor-
areinvolvedineveryaspectofprostateembryogenesis,and beta (TGF-𝛽). Among the cells with M2 phenotype, the
inagingmenwithprostatichyperplasia.Likewise,androgen tumor-associatedmacrophages(TAMs)havebeenshownto
deprivationatanyphaseoflifecausesadecreaseinprostate becapableofsecretingproteasesthatenhanceinvasionand
cell number and DNA content. The downstream control metastases,togetherwitharangeofcytokinesinhibitingan
mechanisms by which hormonal signals are translated into adaptive tumor-specific immune response, and angiogenic
differentiation, growth, and prostate function in elderly factors that increase neovascularity. It has been ascertained
men are still unraveled [81, 82]. While many studies have that phagocytosis is also unimpaired in the elderly [91].
exploredtherelationshipbetweenprostatecancerandserum Although macrophages are usually found located around
androgens, the association remains ill-defined and clinical necrotic areas of tumor and the advancing tumor margin,
implications are difficult to recognize. Age remains one of theirroleinprostatecancerstillremainscontroversial.While
the main factors that complicate the interaction between it was originally thought that the main function of TAMs
prostate malignancy and serum hormone levels, mainly as was direct cytotoxic effects on tumoral cells, phagocytosis
testosterone levels begin to decrease in the ageing man apoptotic/necroticcelldebris,andpresenttumor-associated
coincidentally as the incidence of prostate cancer starts to antigens to T-lymphocytes, current evidence suggests that
increase.Pierorazioetal.evaluatedtherelationshipbetween inflammation and TAMs can also promote tumor growth
testosteronelevelsandthedevelopmentofhigh-riskprostate and metastasis. The density, size, and location of tumor
cancerandfoundthathigherlevelsofserumfreetestosterone infiltratingmacrophagesinprostatecancerhavebeenshowed
are associated with an increased risk of aggressive prostate as powerful predictors of patient outcome, and prostate
cancer among older men [83]. They concluded that higher cancer specimens’ harbor increased positive cells express-
levels of serum free testosterone are associated with an ing the macrophage specific marker CD68 compared to
CurrentGerontologyandGeriatricsResearch 5
benign glands [92–94]. Additionally, it was demonstrated BPH, and prostatic cancer [103]. It has been observed that
that expression of macrophage colony-stimulating factor PIA lesions are associated with chronic inflammation of
(M-CSF)anditsreceptorcolony-stimulatingfactor-1recep- the prostate, and histological transitions have been noted
tor (CSF-1R) are increased in primary tumors of patients betweenareasofPIAandhigh-gradeprostateintraepithelial
exhibiting metastatic disease [95]. Shirotake et al. showed neoplasia (HGPIN) and between PIA and prostate cancer
that both high monocyte chemoattractant protein-1 (MCP- [104].Theinflammatoryinfiltratesaremainlyrepresentedby
+ +
1) expression and high macrophage infiltration in prostate CD3 T-lymphocytes (70–80%, mostly CD4 lymphocytes)
+ +
cancer specimens correlate with a high prostate-specific andCD19 orCD20 B-lymphocytes(nearly,10–15%)[105].
antigen(PSA)recurrencerateandthatAT1Rblockade(ARB) In the normal prostate, the infiltrates around the periglan-
inhibits MCP-1 expression through the PI3K/Akt pathway dular area are mainly composed of T-lymphocytes (70%
+
and blocks macrophage infiltration in castration-resistant CD8 cells), while lymphoid aggregates are located in the
prostatecancer[96].Nonomuraetal.[97]foundthatTAM fibromuscular stroma. These aggregates, mainly consisting
infiltration was significantly correlated with serum PSA of B-lymphocytes follicles surrounded by parafollicular T-
+
level, Gleason score, and clinical stage. Shimura et al. [98] lymphocytes with CD4 cells, are two times more frequent
+
demonstratedtheassociationbetweenTAMinfiltrationand than CD8 cells. In the adult prostate, a different inflam-
disease-free survival after radical prostatectomy. They also matory infiltrate pattern has been described in relation
examinedtheassociationbetweenTAMinfiltrationandthe to the type and extension of inflammation. Robert et al.
rateofdetectionofprostatecanceratarepeatbiopsyofthe [106] showed that, in 282 patients with BPH, there was an
prostate in patients in whom the first biopsy was negative. inflammatory infiltrate constituted by T-lymphocytes (i.e.,
+
They found no difference in TAM count between the cases CD3 cells) in the 80% of cases associated with 52% of
+
withorwithoutprostatecancer.Bycontrast,themacrophage antigen-presenting cells, including B-lymphocytes (CD20
scavengerreceptor-(MSR-)positiveinflammatorycellscount cells).Incontrast,asignificantdecreaseinthecountsofthese
in patients with cancer was significantly lower than that in cellswasobservedinhigh-gradeprostaticcancercompared
+
patientswithoutcancerattherepeatbiopsy.Logisticregres- toBPH[105].TheincreaseddensityofCD3 T-lymphocytes
sion analysis indicated that the MSR count at first biopsy inBPHsuggeststhattheinitialresponsetocellulardamageis
is a significantly better predictive factor for positive repeat mediatedbycell-mediatedimmunity.Thedecreaseddensity
biopsy than PSA velocity, interval between first and repeat of immune cells in high-grade prostatic cancer may reflect
biopsies,orTAMcount.DecreasedinfiltrationofMSR-posi- immunosuppression. Recently, Fujii et al. found no signifi-
tive inflammatory cells in negative first biopsy specimens cant difference in the number of infiltrating T-lymphocytes
was correlated with positive findings in the repeat biopsy. betweenbenignandmalignanttumors;however,thenumber
MSRcounthasbeen,therefore,proposedasavalidindexto of infiltrating B-lymphocytes was significantly reduced in
avoidunnecessaryrepeatbiopsies[97].Gollapudietal.[99] malignantglands[107].
haverecentlyshownthatmeanTAMnumberwashigherin
cancercoresversusprostaticintraepithelialneoplasia(PIN)
and benign tissue and higher in high-grade prostate cancer 5.TheAntigen-PresentingMachineryin
supporting the potential role of TAMs in prostate cancer ProstateCancer
development.Inastudycomprising38prostatecancers,the
+
presence of CD1a Langerhans cells was associated mainly DefectsinHLAclassIantigen-processingmachinery(APM)
with low-grade prostate carcinoma. Liu et al. [54] found a component expression often have a negative impact on the
+
significantcorrelationbetween lownumbersofCD1a cells clinicalcourseoftumorsandontheresponsetoT-cell-based
and a high Gleason score and pathological stage pT3. The immunotherapy [108]. Aged neutrophils are also less able
+
numbers of CD1a cells were, however, very low in normal to respond to rescue from apoptosis, while aged dendritic
andbenignprostatetissues[54].Otherstudieshave,however, cells (DCs) are less able to stimulate T- and B-lymphocytes
demonstrated variable evidence for TAMs during prostate [109]. The altered T-lymphocyte stimulation is a result of
cancerprogression. changesinhumanleukocyteantigenexpressionandcytokine
production, and lower B-lymphocyte stimulation is a result
of changes in DCs immune complex binding [109]. It is
4.TheAdaptiveImmunityinProstateCancer known that DCs are the most potent, professional antigen-
presentingcellsoftheimmunesystem[110].Withtheirability
Ageing is accompanied by alterations to T-lymphocyte tointeractwithB-andT-lymphocytesandtheirwidespread
immunityandalsobyalow-gradechronicinflammatorystate localization, they are a pivotal component of the innate
termed“inflammaging.”Immunecellinfiltrateisaconstant immunesystem.Therecentlydescribedpositiveoutcomeof
featureinnormalprostate,BPH,andprostaticcancer[100]. aclinicaltrialwithT-lymphocyte-basedimmunotherapyin
IthasbeenstatedthattheagedT-cellresponseischaracter- prostatecancerhasstimulatedinterestinthecharacterization
izedbyincreasedproductionofproinflammatorycytokines, oftheAPMcomponentexpressioninprostatecancerlesions,
which could significantly contribute to prostate carcino- sincethis“machinery”playsacrucialroleinthegeneration
genesis through induction of key inflammation-mediated and expression of the trimeric HLA class I surface antigen
prosurvivalfactors[101,102].Husseinetal.investigatedthe complex on tumor cells. Immunohistochemical staining of
cells of the immune system present in normal prostate, a tissue microarray including 59 primary prostate cancers
6 CurrentGerontologyandGeriatricsResearch
lesions and matched normal tissues has shown downregu- in prostate cancer, which will potentially be developed as
lation of all the HLA class I APM components analyzed, a biomarker in prostate cancer. They also provide evidence
although with a different frequency in tumor lesions when thatAKAP-4isapotentialtargetforprostatecanceradoptive
comparedtonormalprostatetissues[108].Aprimaryfinding immunotherapy or antitumor vaccination [117]. Beginning
wasthefrequentlossordownregulationofcalnexinand/or in the early 1990s, several tumor-associated antigen genes
tapasin, which appears to be an independent prognostic including the cancer-testis antigens were identified that
marker of tumor recurrence. In contrast, HLA class I HC exhibited tumor-specific expression. The cancer-testis anti-
expression levels were less affected in primary prostate gens are a group of proteins that are typically restricted to
cancers;thefrequencyofdownregulationdescribedbyBlades the testis in the normal adult but are aberrantly expressed
et al. has been found markedly lower than that reported incancersofunrelatedhistologicorigin[118].Hudolinetal.
by other authors [111] in a large number of prostate cancer observedMAGE-A1in10.8%ofcarcinomasamples,whereas
lesions and that reported in other tumor types. In contrast, multi-MAGE-A and NY-ESO-1/LAGE-1 stained 85.9% and
highfrequenciesoflossordownregulationoflowmolecular 84.8% of samples using immunohistochemistry, suggesting
weightpolypeptides2(LMP2),transportersassociatedwith thatapanelofCTantigensratherthanindividualonesmaybe
antigen processing 1 (TAP1), and tapasin as well as of 𝛽2- morevaluableasbiomarkers[119].Smithetal.suggestedthat
microglobulin were demonstrated in prostate cancer when multiplesynovialsarcomaXchromosomebreakpoint(SSX)
comparedtonormalprostatetissue.ThefrequencyofLMP2, proteinsareexpressedinmetastaticprostatecancers,which
TAP1,andtapasindownregulationishigherthanthatfound areamenabletosimultaneoustargeting[120].
in lung, colorectal, hepatocellular, cervical, and renal cell Enzalutamide(i.e.,asecond-generationandrogenantag-
carcinoma. In parallel to the findings in head and neck onist) has been recently approved for castration-resistant
squamous cell carcinoma, cervical carcinoma, esophageal prostate cancer treatment. Ardiani et al. showed that enza-
carcinoma, breast carcinoma, and melanoma, the impaired lutamidemediatedimmunogenicmodulationinTRAMP-C2
TAPexpressioninprostatecancerlesionsisassociatedwith cells.Invivo,enzalutamidemediatedreducedgenitourinary
tumor grading, staging, and time to recurrence. Qiu et al. tissueweight,enlargementofthethymus,andincreasedlevels
foundthat,invitro,theprostatecancercellPC-3infectedwith ofT-cellexcisioncircles.BecausenochangeswereseeninT-
+
LentivirusTAP1canefficientlyoverexpressTAP1andtapasin, lymphocytesfunction,asdeterminedbyCD4 T-lymphocyte
andHLA-1wasalsoupregulatedonthesurfaceoftheinfected proliferation and Treg functional assays, enzalutamide was
cells.TheLentivirusTAP1infectionincreasedtheapoptosis determined to be immune inactive [121]. The combination
rateofPC-3cells.Inaddition,withthecoculturePC-3cells of enzalutamide and immunotherapy has been, therefore,
+
andlymphocytes,TAP1augmentedtheexpressionofCD3 suggested as a promising treatment strategy for castration-
+ +
CD8 CD38 cells[112]. resistant prostate cancer. A renewed interest in prostatic
acid phosphatase (i.e., a nonspecific phosphomonoesterase
synthesized in prostate epithelial cells, whose level pro-
6.ImmunotherapyandProstateCancer portionally increases with prostate cancer progression) has
been shown, because of its usefulness in prognosticating
The goals of any cancer therapy are to improve disease intermediate to high-risk prostate cancers and its success
control,palliatepain,andoverallsurvival[113].In2010,the in the immunotherapy of prostate cancer [122]. Based on
American Food and Drug Administration (FDA) approved thegoodprognosticvalueofprostaticacidphosphataseand
the first therapeutic cancer vaccine, called sipuleucel-T, for the potential usefulness of prostatic acid phosphatase as an
the treatment of castration refractory prostate cancer [114, antigen,animmunotherapyemployingautologousprostatic
115]. Different from the currently adopted chemotherapy acid phosphatase-loaded dendritic cells was initiated [123].
drugs that produce widespread cytotoxicity to kill tumor Wada et al. used a well-described genetically engineered
cells, anticancer vaccines and immunotherapies focus on mouse, autochronous prostate cancer model to explore
empowering the immune system to overcome the tumor. It the relative sequencing and dosing of anti-cytotoxic T-
hasbeenshownthatprostatecancerisanidealmodelforcan- lymphocyte-associated antigen-4 (CTLA-4) antibody when
cer vaccine development. This is mainly due to its humoral combinedwithacell-based,granulocytemacrophagecolony-
and cellular immunity to a range of cancer antigens, which stimulatingfactor-(GM-CSF-)secretingvaccine[124].These
aregoodcandidatesforvaccinetherapytogeneratearobust experiments corroborate recent clinical data, which suggest
antitumor response. Recently, Cheema et al. suggested the that the combination of CTLA-4 blockade and cell-based,
potential application of BORIS (i.e., a cancer-testis antigen GM-CSF-secretingvaccinesmayhavesignificantantitumor
normally present at high levels in the testis and aberrantly effectsinmenwithprostatecancer.Thesedataalsoindicate
expressed in various tumors and cancer cell lines) as a that the “therapeutic window” of such an approach may
biomarkerforprostatecancerdiagnosis,animmunotherapy be maximized through meticulous study of various dosing
target, and, potentially, a prognostic marker of aggressive regimens.Additionally,futureclinicalstudiesmayfindthat
prostate cancer [116]. The ability of BORIS to activate the theadditionofcyclophosphamidetothistreatmentstrategy
androgen receptor gene suggests its involvement in the allowsforreductioninthedoseofanti-CTLA-4,potentially
growth and development of prostate cancer [116]. Chiriva- limitingautoimmunetoxicity.InarecentphaseItrial,Perez
Internati et al. first reported the aberrant expression of the etal.demonstratedthattheAE37vaccineissafeandinduces
cancer-testis antigen A-kinase anchor protein-4 (AKAP-4) HER-2/neu-specificimmunityinaheterogeneouspopulation
CurrentGerontologyandGeriatricsResearch 7
+
of HER-2/neu prostate cancer patients [125]. Clusterin is etal.showedasignificantincreaseininfiltratinginflamma-
a cytoprotective chaperone protein that is overexpressed torycellsincludingmacrophagesintheprostatesofagedmice
in many tumor types and is upregulated in response to [38], reflecting the prominent role for immune cells during
cellular stress caused by cancer treatments, including hor- theagingprocess,whichislinkedtoprostatecancerdevelop-
monalmanipulation,radiation,andchemotherapy.Custirsen ment.Identifyingcontributingfactorsinthetumormicroen-
is known as a second-generation antisense oligonucleotide vironment, which modulate this cleavage event on tumor
that is complementary to clusterin mRNA and potently cells, is necessary for determining alternative therapeutic
suppresses clusterin expression in preclinical models of targetsforamultimodalityapproachtoinhibittheinvasion
prostate cancer as well as in clinical trials. The innova- stepsofmetastasis.Despitethetechnicaladvantagesoffered
tive first-in-human phase I neoadjuvant trial demonstrated byroboticsystemsandothertechniques,thediagnosticpro-
dose-dependent plasma and prostate tissue concentrations cessrequiresfurtherimprovement.Itisknownthatprostate
of custirsen, which was well tolerated at all dose levels cancerconsistsofdistinctsubpopulationsofcancercells,each
[126]. Results from the clinical trials (i.e., sipuleucel-T- withitsowncharacteristicsensitivitytoagiventherapeutic
based vaccine, GVAX-prostate cancer, viral prostate cancer agent.Cancertherapiescanbeseenasfiltersthatremovethe
vaccines,DNA-basedvaccines,andgene-mediatedcytotoxic sensitivesubpopulationsbutallowinsensitivesubpopulations
immunotherapy) indicate that prostate cancer vaccines are to escape. The combined efforts of urologists, pathologists,
generally safe and, encouragingly, capable of generating gerontologists, and biologists can contribute much towards
tumor-specific T-lymphocyte responses. It is becoming evi- improving our understanding of the complexity of prostate
dent that prostate cancer patients with early-stage disease cancer, and such a multidisciplinary approach will help to
maybethosewhoobtainthemainbenefitsfromvaccines. clarifyexistingconcepts,categorizecurrentknowledge,and
suggestalternativeapproachestothediscoveryofbiomarkers
andpredictivevaluesthaturgentlyneedtobetranslatedinto
7.ConcludingRemarks clinicalpractice.
The primary risk for prostate cancer is aging, often associ- ConflictofInterests
ated with inflammation (Figure2). Inflammation results in
a tissue microenvironment that alters the normal prostate The authors declare that there is no conflict of interests
epithelialcelldifferentiationprogramandthatacceleratesthe regardingthepublicationofthispaper.
initiation of prostate cancer with a basal cell origin [127].
Despite the continuous progress, prostate cancer is one of
Authors’Contribution
themaincancersthataffectmen,especiallyoldermen.This
is largely due to the fact that the tumoral mass cannot be GianluigiTavernaandFabioGrizzicontributedequallytothe
identifiedusingcurrentimagingtechniques.Prostatecancer paper.
can only be diagnosed on the basis of increased PSA levels
associatedwithalowaccuracyofthebiopsyfragmentsand
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