Emerging Hallmark Of Gliomas Microenvironment in Evading Immunity: A Basic Concept Part 1
Jul 27, 2023
Abstract
Keeb kwm
Xyoo kaum xyoo dhau los, txij li kev sim tshuaj ntsuam xyuas cov hom phiaj kho mob rau gliomas tsis tau ua kom pom qhov muaj txiaj ntsig ntawm kev muaj sia nyob, qhov tseem ceeb tsis ntev los no tau hloov mus rau cov tswv yim tshiab rau kev hloov kho lub cev tiv thaiv kab mob thiab lawv cov microenvironments (TME). Cov kab mob qog noj ntshav muaj kaum ib lub cim uas ua rau lawv txawv ntawm ib txwm muaj, ntawm cov uas yog kev tiv thaiv kab mob. Kev tiv thaiv kab mob hauv glioblastoma pab nws khiav tawm ntau yam kev kho mob.
Nyob rau hauv xyoo tas los no, nrog rau kev txhim kho ntawm kev tshawb fawb thiab thev naus laus zis thiab kev tshawb fawb txog kev kho mob tob zuj zus, ntau thiab ntau tus neeg tau pib mob siab rau kev kho mob thiab tiv thaiv kev mob qog noj ntshav. Ntawm lawv, glioma, raws li ib qho mob qog nqaij hlav, tau txais kev saib xyuas ntau. Nyob rau hauv tus txheej txheem ntawm kev kho glioma, lub hom phiaj kev kho mob thiab immunotherapy yog tam sim no kev tshawb fawb hotspots. Kab lus no yuav tshawb txog kev sib raug zoo ntawm glioma lub hom phiaj thiab kev tiv thaiv kab mob, thiab tshawb nrhiav nws txoj kev cia siab rau kev kho mob glioma los ntawm qhov pom zoo.
Glioma yog ib qho qog uas tshwm sim hauv lub hlwb thiab tus txha caj qaum, thiab nws txoj kev kho mob ib txwm yog qhov nyuaj hauv kev tshawb fawb kho mob. Tam sim no, cov kev kho mob uas nquag siv suav nrog kev phais phais, xov tooj cua, thiab kev siv tshuaj khomob. Txawm li cas los xij, cov txheej txheem no muaj qee qhov kev txwv, xws li kev phais mob nyuaj, kho tus nqi qis, kev siv hluav taws xob mus sij hawm ntev thiab kev siv tshuaj khomob yuav ua rau muaj kev phiv, thiab lwm yam. Yog li ntawd, nws yog ib qho tseem ceeb tshwj xeeb los nrhiav kev kho kom zoo dua.
Targeted therapy yog hais txog kev siv cov tshuaj tshwj xeeb los cuam tshuam thiab tswj kev loj hlob thiab faib cov qog nqaij hlav cancer kom cov hlwb tsis tuaj yeem ua cov metabolism hauv ib txwm thiab muaj sia nyob. Hauv kev kho mob ntawm glioma, lub hom phiaj tseem ceeb ntawm kev kho mob muaj xws li EGFR, VEGF, thiab lwm yam. EGFR thiab VEGF yog cov proteins tsim nyog rau kev ua kom cov hlwb glioma, thiab lawv ua lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm qog. Yog li, inhibiting kev qhia ntawm EGFR thiab VEGF tuaj yeem cuam tshuam kev loj hlob thiab kev sib kis ntawm cov qog hlwb.
Txawm li cas los xij, kev kho cov phiaj xwm tsis tuaj yeem tshem tawm cov qog hlwb, thiab nws txoj kev kho mob tsuas yog txwv. Nyob rau hauv cov ntaub ntawv no, immunotherapy yog ib qho tseem ceeb heev raws li ib tug ntxiv rau cov hom phiaj kho. Immunotherapy ua tiav lub hom phiaj ntawm kev kho cov qog los ntawm kev txhim kho kev ua haujlwm ntawm lub cev tiv thaiv kab mob, ua kom muaj zog thiab ntxiv dag zog rau lub cev tiv thaiv kab mob rau cov qog hlwb. Hauv kev kho mob ntawm glioma, kev siv tshuaj tiv thaiv kab mob tuaj yeem txhim kho lub cev tiv thaiv kab mob, txo cov qog nqaij hlav, thiab txo cov kev mob tshwm sim ntawm kev kho mob.
Tsis tas li ntawd, nyob rau hauv xyoo tas los no, tib neeg kuj tau pib ua tib zoo mloog rau kev sib koom ua ke ntawm kev kho mob thiab kev tiv thaiv kab mob. Cov kev tshawb fawb tau pom tias qhov kev kho mob sib xyaw ua ke no tuaj yeem muab kev ua si tag nrho rau qhov zoo ntawm ob txoj kev kho mob, txhim kho cov nyhuv kho, thiab txo qhov tsis zoo ntawm kev kho mob. Qee qhov kev sim kev tshawb fawb kuj pom tau tias kev sib xyaw ua ke ntawm kev siv cov phiaj xwm kev kho mob thiab kev tiv thaiv kab mob tuaj yeem ua rau muaj kev cuam tshuam ntawm cov qog hlwb thiab txhim kho kev tiv thaiv kab mob tua, uas xav tias yuav dhau los ua kev kho mob ntawm glioma.
Hauv kev xaus, kev sib raug zoo ntawm glioma lub hom phiaj thiab kev tiv thaiv kab mob yog qhov hotspot hauv kev tshawb fawb kho mob tam sim no. Txawm hais tias qhov kev kho mob no tseem nyob hauv nws cov me nyuam mos, nws muaj peev xwm zoo thiab cuam tshuam tseem ceeb rau kev kho mob ntawm glioma. Peb ntseeg tias tsis ntev, kev sib xyaw ua ke ntawm glioma lub hom phiaj thiab kev tiv thaiv kab mob yuav ua rau muaj kev cuam tshuam zoo dua hauv kev kho glioma. Los ntawm qhov kev xav no, peb yuav tsum txhim kho peb txoj kev tiv thaiv, thiab Cistanche tuaj yeem txhim kho kev tiv thaiv zoo. Vim tias cov nqaij minced muaj ntau yam tshuaj antioxidant, xws li vitamin C, vitamins, carotenoids, thiab lwm yam, cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals, txo oxidative kev nyuaj siab, thiab txhim kho kev tiv thaiv ntawm lub cev.
Nyem cistanche tubulosa cov txiaj ntsig
Cov ntsiab lus
Glioblastoma's TME yog tsim los ntawm ntau yam array ntawm cellular lam, xws li los ntawm peripherally derived ntawm lub cev tiv thaiv kab mob mus rau ntau yam kab mob-nyob rau hauv tshwj xeeb cell hom. Piv txwv li, cov ntshav-hlwb barrier (BBB) ua hauj lwm raws li ib tug xaiv barrier ntawm lub systemic ncig thiab lub hlwb, uas zoo cais nws los ntawm lwm yam ntaub so ntswg. Nws muaj peev xwm thaiv tau ib ncig ntawm 98 feem pua ntawm cov molecules uas thauj cov tshuaj sib txawv mus rau lub hom phiaj qog.
Lub hom phiaj
Lub hom phiaj ntawm daim ntawv no yog muab cov lus qhia luv luv ntawm kev siv tshuaj tiv thaiv kab mob thiab yuav ua li cas 'ntse' gliomas zam lub cev tiv thaiv kab mob txawm tias nrhiav pom ntawm immunotherapy rau glioma.
Cov lus xaus
Ntawm no, peb qhia txog kev sib cuam tshuam ntawm cov qog nqaij hlav, TME, thiab cov qauv nyob ze ze ua rau nws nyuaj rau kev nkag siab yuav ua li cas mus cuag cov qog nws tus kheej. Ntau tus kws tshawb fawb tau pom tias lub hlwb TME yog tus tswj xyuas qhov tseem ceeb ntawm kev loj hlob ntawm glioma thiab kev kho mob zoo.
Ntsiab lus
Glioma, Glioblastoma, Microenvironment, Immune Evasion, Immunotherapy.
Keeb kwm
Gliomas yog ib qho ntawm cov kab mob loj tshaj plaws hauv nruab nrab paj hlwb (CNS). Ib tug glioma yog categorized raws li nws histogenesis rau hauv tus qauv WHO Qib I-IV [1, 2], nrog rau qib III-IV hu ua high-grade glioma (HGG) [3]. Tsis ntev los no, Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb (WHO) tau ntxiv phenotypic thiab genotypic yam ntxwv rau kev faib [2]. Glioblastoma multiforme (GBM), uas yog hom glioma uas hnyav tshaj plaws, muaj qhov tshwm sim tsis zoo. Txawm hais tias muaj cov kev xaiv kho mob niaj hnub no, qhov nruab nrab ntawm kev muaj sia nyob tsis pub muaj sia nyob (PFS) yog 7–8 lub hlis thiab ib xyoos 5-xyoo tag nrho cov ciaj sia taus (OS) ntawm 9.8 feem pua [4].
Kev tawm tsam rau kev kho tus qauv hauv malignant gliomas tau raug piav qhia ntau zaus [5–8]. Hanahan thiab Weinberg [9] tau tshaj tawm txog rau lub ntsiab lus ntawm kev mob qog noj ntshav hauv xyoo 2000, suav nrog lub peev xwm los txhawb kev loj hlob ntawm cov teeb liab, dodge kev loj hlob suppressors, txhawb kev ntxeem tau thiab metastasis, ua kom muaj kev tsis txawj tuag, ua rau angiogenesis, thiab tiv thaiv kev tuag ntawm tes. Ntau xyoo tom qab, ntxiv plaub lub ntsiab lus tau npaj los txhawb txoj kev xav ntawm kev mob qog noj ntshav [10].
Ntawm Hanahan thiab Weinberg kaum ib tus yam ntxwv, qhov txaus nyiam tshaj plaws yog qhov muaj peev xwm tiv thaiv kev tiv thaiv kab mob [10]. Lub peev xwm tshwj xeeb no yog qhov tshwm sim ntawm kev sib cuam tshuam ntawm cov khoom ntawm cov qog microenvironment (TME). TME ntawm gliomas yog kev tiv thaiv kab mob thiab muaj ntau yam kev ciaj sia [11]. Nkag siab txog kev ua haujlwm ntawm TME hauv glioma tiv thaiv kab mob yuav muaj txiaj ntsig rau ob tus kws tshawb fawb thiab kws kho mob vim nws yuav tso cai rau kev nce qib ntawm kev kho mob niaj hnub rau kev tswj hwm ntawm HGG.
Kev nthuav qhia kho mob
Mob taub hau yog cov tsos mob feem ntau ntawm cov qog hlwb, thiab 1-2 ntawm 1000 cov neeg mob uas mob taub hau tom qab kuaj pom muaj mob hlwb [12, 13]. Cov yam ntxwv sib txawv raws li nws qhov chaw, qhov loj me, thiab kev loj hlob tus nqi. Exacerbated ntawm waking li vim yog txoj hauj lwm supine, thiab kuj los nag los ntawm hnoos los yog Valsava maneuver. Qhov tshwm sim ntawm cov qog hlwb hauv lub hlwb yog nce ntxiv yog tias mob taub hau nce ntau zaus thiab mob hnyav thiab tom qab kev loj hlob ntawm lwm cov tsos mob neurological lossis cov cim qhia [12].
Ozawa et al. qhia tias mob taub hau nrog rau qhov tsis muaj zog lossis kev paub tsis meej, tshwj xeeb tshaj yog nyob rau hauv lub lobe pem hauv ntej, ua rau muaj qhov tshwm sim ntawm cov qog hlwb 44-fold lossis 59-fold, feem [13]. Kev qaug dab peg yog qhov tshwm sim thib ob uas tshwm sim hauv kwv yees li 20 feem pua ntawm cov neeg mob, ua raws li kev qaug zog (1.5 feem pua), thiab tsis meej pem (1.4 feem pua) [13].
Kev kwv yees
Lub sijhawm muaj sia nyob ib txwm rau cov neeg laus hnub nyoog qis dua 70 xyoo uas tsis tau txais kev kho mob rau qib siab glioma yog kwv yees li 3-4.5 lub hlis [14]. Tom qab ntawd, cov txheej txheem biopsy ua raws li kev siv tshuaj khomob, nrog lossis tsis muaj xov tooj cua, txhawb kev ciaj sia mus txog li 8-10 lub hlis ntawm qhov nruab nrab. Cov ciaj sia taus yog 27-31 feem pua ntawm 2 xyoos thiab 7-10 feem pua ntawm 5 xyoos thaum kev kho mob siab tshaj plaws nrog rau kev phais thiab kev kho mob chemoradiotherapy [15].
Lub sijhawm muaj sia nyob nruab nrab rau cov neeg laus uas tau txais kev saib xyuas zoo tshaj plaws tsuas yog tsawg dua 4 lub hlis [14, 15]. Hauv cov neeg mob ntau dua 65 xyoo uas tau kuaj xyuas qhov biopsy lossis resection, hypofractionated irradiation, thiab chemotherapy ua rau lub sijhawm muaj sia nyob nruab nrab ntawm 7-9 lub hlis, tsis zoo li hluav taws xob ib leeg [16,17]. Txawm hais tias muaj pov thawj ntawm cov txiaj ntsig muaj sia nyob, kev suav nrog cov tshuaj kho mob ntxiv tsis cuam tshuam rau lub neej zoo ntawm pab pawg no [15, 17]. Vim yog qhov tsis zoo ntawm glioblastoma, cov neeg mob yuav tsum raug qhia kom tsim nyog txog qhov muaj feem cuam tshuam ntawm kev kho mob ntawm lub neej zoo, ntxiv rau cov txiaj ntsig muaj sia nyob, tshwj xeeb tshaj yog cov neeg laus thiab cov neeg ua haujlwm tsis zoo, uas muaj cov tsos mob tshwj xeeb tsis zoo [ 14, 16] ib.
Cov qog microenvironment
Cov qog nqaij hlav cancer
Lub qog yog tsim los ntawm ntau hom hlwb, thiab ntau dua li hauv cov qog nqaij hlav cancer. Thaum ntxov ntawm lawv txoj kev loj hlob, cov qog nqaij hlav cancer pib ua homogeneous nkaus xwb kom muaj ntau haiv neeg tom qab. Qhov tshwm sim ntawm cell heterogeneity yog tshwm sim los ntawm caj ces tsis ruaj khov, uas txhawb kev tsim ntawm cov cell subpopulations [10, 18].
Lub cev tiv thaiv kab mob
Macrophages yog cov tshuaj tiv thaiv kab mob feem ntau pom hauv glioma [18], ua rau kwv yees li 30 feem pua ntawm cov qog loj [19]. Macrophages nyob rau hauv lub hlwb qog tej zaum yuav yog cov ntaub so ntswg-nyob microglia los yog pob txha pob txha macrophages (BMDM). Microglia yog tsim nyob rau hauv lub embryonic txoj kev loj hlob [20, 21], whereas BMDMs yog tam sim no thaum lub homeostasis ntawm lub paj hlwb raug cuam tshuam los ntawm ib tug tshwj xeeb pathological xeev [22]. Nyob rau hauv lub xub ntiag ntawm lub hlwb qog, ib qho kev cuam tshuam cov ntshav-hlwb barrier (BBB) yog hypothesized los pab rau kev nrhiav neeg ntawm peripherally circulating monocytes rau hauv cov qog loj [23]. Cov qog-uas txuam nrog macrophages thiab microglia (TAMs) yog tsim los ntawm ob hom macrophages [19]. TAMs yog cov hlwb pro-tumorigenic uas loj hlob tuaj raws li qib qog nce [24, 25]. Txawm hais tias lawv lub hauv paus los ua macrophages, TAMs tsim ob peb cov cytokines proinflammatory thiab tsis muaj txiaj ntsig zoo hauv stimulating T hlwb [26].
Dendritic cell
Dendritic cells (DCs) yog cov hlwb koom nrog hauv kev soj ntsuam cov kab mob thiab kho cov kab mob microenvironmental puas tsuaj [27]. DCs ua rau lub cev tiv thaiv kab mob los ntawm engulfing qog antigens thiab nthuav tawm rau T thiab B-cells [28]. DCs muaj ntau dua nyob rau hauv vascular-nplua nuj compartments xws li choroid plexus thiab meninges es tsis yog nyob rau hauv lub hlwb parenchyma. Qhov no qhia tau hais tias muaj peev xwm ntawm peripheral DCs tsiv mus rau hauv CNS ntawm cov hlab ntsha-nplua nuj compartments [29, 30]. DCs tuaj yeem nkag mus rau hauv lub hlwb thiab tus txha caj qaum los ntawm afferent lymphatics lossis venules nyob rau hauv lub xub ntiag ntawm pathological mob, xws li mob qog noj ntshav [31]. DCs tuaj yeem kuaj pom thiab nthuav tawm cov qog antigens rau T hlwb hauv cov qog nqaij hlav hauv lub ncauj tsev menyuam sib sib zog nqus los ua kom muaj kev sib koom tes T-cell-mediated teb [31]. DCs tso tawm cov exosomes uas nthuav tawm cov qog los yog cov tshuaj tiv thaiv stimulatory los ua kom Cytotoxic T-cell cov lus teb-ib qho yeeb yam antagonized los ntawm qog-cell-derived exosomes [32].
Ntshav-brain barrier (BBB)
Endothelial cells (EC), extracellular matrix (ECM), astrocytes, thiab pericytes suav nrog BBB [33]. EC yog kaw nrog nruj junctions thiab ciam teb los ntawm ECM raws li basal lamina. Ntawm lub basal lamina sab nrauv, astrocyte kawg taw thiab pericytes ua tiav BBB [34]. BBB txoj kev tswj hwm nruj dhau ntawm cov tshuaj thiab cov hlwb mus rau hauv thiab tawm ntawm lub hlwb [35, 36] yuav so kom txaus nyob rau hauv cov kab mob pathologic kom tso cai nkag mus rau qee lub cev tiv thaiv kab mob [35, 37]. Hauv gliomas, BBB kev ncaj ncees tsis muaj zog vim yog cov qog nqaij hlav siab metabolic.
Xws li cov xwm txheej ceev vasculogenesis, uas ua rau tsim cov hlab ntsha tortuous [38, 39]. Cov hlab ntsha tsis zoo no yuav ua rau muaj kev cuam tshuam ntawm hypoxia thiab acidic microenvironment. Interestingly, no ostensibly detrimental lub xeev txhawb qog kev loj hlob es tsis txhob rhuav tshem nws cov hlwb [19, 40, 41]. Tsis tas li ntawd, lub xub ntiag ntawm lub paj hlwb disintegrates astrocytic kawg taw thiab pericytes, ua rau ib tug leaky BBB [42]. Lub kaw ntom nti ntawm cov endothelial cell (EC) paub tias yuav raug cuam tshuam hauv GBM los ntawm kev ua haujlwm ntawm vascular endothelial kev loj hlob yam (VEGF) [43, 44].
Kev tiv thaiv kab mob
Gliomas ua rau lub cev tsis muaj zog los ntawm ntau txoj kev. Gliomas tuaj yeem tso tawm cov tshuaj tiv thaiv kab mob uas muaj ntau yam tshwm sim, suav nrog kev hloov kho ntawm qhov loj histocompatibility complex (MHC), kev txhawb nqa ntawm DCs tsis paub qab hau li antigen-presenting cells (APCs) [45], thiab kev loj hlob ntawm kev tswj T (Treg) hlwb [39] , 40] ib. Siv chemokines, glioma kuj ua rau T-cell anergy, inhibits ntuj killer (NK) hlwb, induces T-cell tuag, thiab recruits immunosuppressive T hlwb [46]. Txhua txoj hauv kev no feem ntau cuam tshuam, ua rau lub voj voog tsis zoo uas txhawb nqa glioma ciaj sia.
Immunosuppressive yam
Nws yog qhov zoo-tsim tias gliomas tso cov tshuaj tiv thaiv kab mob los tiv thaiv lub cev tiv thaiv kab mob [45]. Nws kuj tseem paub tias qhov tso tawm ntawm cov tshuaj no txhawb kev loj hlob ntawm Treg hlwb. Txhua qhov kev hloov pauv uas tsim los ntawm cov tshuaj tiv thaiv kab mob zais cia tom qab yuav ua rau tsis zoo rau kev ua haujlwm ntawm cytotoxic T lymphocytes (CTLs) [38, 40, 41]. Interleukin-10 (IL-10), interleukin-6 (IL-6), transforming growth factor (TGF), thiab prostaglandin E-2 (PGE{{10}) }}) yog cov kev tshawb fawb tshaj plaws hauv kev tiv thaiv kab mob hauv glioma microenvironment. Txawm hais tias TAMs yog lub hauv paus generators ntawm cov tshuaj no [49–51], nws tau pom tias cov glioma hlwb secrete cov yam tseem ceeb thiab [52].
Glioma kuj tau nruab nrog Glycoprotein A repetition predominant (GARP), qhov chaw molecule paub los ua kom Treg hlwb, raws li qhia nyob rau hauv kev tshawb fawb ntawm histopathological specimens ntawm qib qis astrocytomas thiab glioblastomas. GARP exerts nws immunoregulatory muaj nuj nqi los ntawm inducing Treg hlwb los ntawm kev pab ntawm TGF-ß thiab kuj los ntawm inhibiting lub proliferation ntawm Cytotoxic T hlwb [53, 54].
Down-regulation ntawm MHC
MHC yog ib qho molecule koom nrog hauv kev nthuav qhia antigen; Nws yog feem ntau cais raws li kuv thiab II, nrog rau yav dhau los tau qhia feem ntau ntawm cov hlwb nucleated thiab tom kawg ntawm APCs. Class I MHC khi rau hauv cov tshuaj tiv thaiv kab mob peptides thiab thauj lawv mus rau ntawm lub xov tooj ntawm tes, qhov chaw uas lawv tau lees paub los ntawm CTL [55]. Class I MHC qhia tau ploj hauv ze li 50 feem pua ntawm 47 GBM cov qauv, raws li ib txoj kev tshawb fawb [56]. Muaj kev sib raug zoo ntawm HLA chav kawm I antigen poob thiab qog qog [57]; qhov piv txwv yog qhia hauv daim duab 1a, thiab. Immunosuppressive cytokines xws li TGF- thiab IL-10 raug txiav txim siab los txwv kev qhia ntawm Class I MHC.
Cov cytokines no tsis tsuas yog cuam tshuam cov kev nthuav qhia antigen nkaus xwb tab sis kuj txhawb kev qhia ntawm Programmed Death-1 (PD-1) receptor ntawm invading T hlwb. Qhov receptor no yuav khi rau qog cell-expressed PD-1 ligands (PD-L1) thiab tsim T-cell anergy [58]; ib qho analogous yog illustrated nyob rau hauv daim duab 1c, thiab. Cov nyhuv ntawm cov tshuaj tiv thaiv kab mob cytokines thiab kev sib cuam tshuam ntawm PD-1 thiab nws cov ligand yuav tau tham ntau dua tom qab hauv nqe lus no. Class II MHC kev qhia kuj txo qis hauv glioma-associated microglia (GAM) raws li kev cuam tshuam ntawm cytokines [59, 60].
Kev ua haujlwm tsis zoo DC
DCs muab tau los ntawm cov hlwb myeloid yog thawj zaug tsis tau cog lus rau kev nthuav qhia antigen. Ntau yam stimuli yuav muab faib ua DCs ua ob hom phenotypes: hom -1 thiab hom -2 polarized effector DCs (cDC1 thiab cDC2, feem) [61]. Te cDC1s tuaj yeem qhib CTLs ntawm Class I MHC, qhov cDC2s tuaj yeem qhib T pab hlwb ntawm Class II MHC [62, 63]. Ntau yam chemokines xws li CCL5 thiab XCL1 nrhiav cDC1s rau hauv TME [64], qhov uas lawv siv cov qog antigen los txhawb CTL ntawm cov qog ntshav [65, 66] lossis tso cov tshuaj chemokine ncaj qha mus nrhiav CTL rau hauv cov qog [67, 68. ].
Txawm li cas los xij, muaj TGF- thiab PGE-2 hauv GBM's TME hloov DCs mus rau qhov kev tswj hwm phenotype, uas txhawb nqa Treg proliferation es tsis txhob CTLs [69]. Tsis tas li ntawd, nws yog kev xav tias IL-6 thiab IL-10 tsim los ntawm microglia thiab TAMs [38, 39, 61] cuam tshuam DC maturation thiab es tsis txhob txhawb DC tsis paub qab hau kom loj hlob [45].
Sib nrug los ntawm lawv tsis muaj peev xwm xa cov antigen rau T hlwb [71], DC tsis paub qab hau tsim TGF-, uas ua rau muaj kev tiv thaiv kab mob ntau dua hauv glioma microenvironment [45].
Immunosuppressive TAMs
TAMs li non-inflammatory hlwb ua raws li cov pa dichotomy ntawm macrophage phenotypes, M1 thiab M2 [72]. Raws li qhov kev xav no, macrophages yuav tau txais cov yam ntxwv sib txawv hauv kev teb rau cov kev xav uas lawv ntsib. Interferon- (IFN- ), lipopolysaccharides (LPS) [73], thiab granulocyte-macrophage colony-stimulating factor (GM-CSF) [74], tag nrho induce macrophages los txais yuav M1 phenotype, uas yog ib qho tseem ceeb hauv kev tsim T pab hom. 1 (T1) hlwb [73] thiab pro-inflammatory cytokines [75].
Ntawm qhov tod tes, M2 macrophages txhawb T2 lymphocytes, angiogenesis, thiab qog loj hlob [76]. Qhov kev coj cwj pwm no muaj feem xyuam rau qib qis ntawm IL-12 thiab IL-23 thiab qib siab ntawm IL-10 thiab TGF- . M2-phenotypes kuj raug ntxias los ntawm Macrophage Colony-Stimulating Factor (M-CSF) [74], thiab IL-34 [75]. M-CSF thiab IL-34 ob leeg txhawb nqa mitogen-activated protein kinase (MAPK) taw qhia txoj hauv kev ntawm CD115 receptor [75].
Txoj hauv kev MAPK tswj ntau yam txheej txheem tseem ceeb rau kev ciaj sia ntawm tes [77]. IL-10 [78] yog ib qho ntawm MAPK txoj hauv kev kawg cov khoom lag luam, txij li nws tsav T cell sib txawv rau hauv T2 hlwb, li no ua rau kev tsim cov tshuaj tiv thaiv cytokines [79]. Macrophages nyob rau hauv lub glioma TME raug cais raws li M2 vim hais tias lawv muaj ib tug siab ntawm anti-inflammatory thiab pro-angiogenic yam tseem ceeb (Fig. 2) [24].
Natural killer (NK) cell inhibition
NK hlwb yog cov lymphocytes loj loj uas, sib piv rau CTLs, tshem tawm cov kab mob uas tsis muaj cov tshuaj tiv thaiv ua ntej (Fig. 2). NK hlwb tuaj yeem txheeb xyuas cov hlwb "ntseeg" uas txo qis-tswj Class I MHC kom tsis txhob muaj kev txheeb xyuas los ntawm CTL. Qhov peev xwm no yog li tseem ceeb heev rau kev tiv thaiv qog nqaij hlav [80].
Hauv vivo cov kev tshawb fawb tau tshaj tawm tias NK hlwb tsis tshua muaj nyob hauv lub hlwb [81], tab sis tuaj yeem nce tus lej thaum BBB qhov kev ncaj ncees tsis zoo, xws li hauv kab mob autoimmune lossis kab mob [82–{2}}]. Tsis tas li ntawd, lub xub ntiag ntawm CX3CL1, ib tug chemokine generated los ntawm neurons, attracts NK hlwb [87]. Lub xub ntiag ntawm NK hlwb hauv GBM tau qhia tias cov pab pawg ntawm lymphocytes no ua lub luag haujlwm tseem ceeb hauv kev soj ntsuam neoplasm [88].
TGF- yuav inactivate NK hlwb los ntawm downregulating lawv activating receptors [89–91] thiab ligands, li no txo lawv proliferation thiab hloov mus rau hauv pro-tumor innate lymphoid cell (ILC)1-zoo li cov hlwb [92]. TGF- paub txog kev tsim cov NKG2D receptor, ib qho NK activating receptor [89], nws cov blockage tau pom tias ua rau NK hlwb tsis muaj peev xwm ntawm cytotoxicity [93]. Vim nws lub peev xwm los tso tawm TGF-, glioma yog NKG2D tsis txaus [89].
Raws li ib txwm muaj, NK hlwb qhia txog NKp44 receptor, uas tuaj yeem khi rau PDGF-D uas tsim los ntawm feem ntau ntawm GBM hlwb thiab tsim cytokines uas inhibit qog kev loj hlob [94]. NKp44 yog ib qho activating receptor rau NK hlwb uas - ua ke nrog NKp30, NKp46, thiab CD16 - yog cov immunoreceptor tyrosine-based activation motif (ITAM) [95, 96].
Ntawm qhov tod tes, glioma tau pom los qhia txog qib siab ntawm Galectin [97], ib tsev neeg cov protein uas tau pom los txhawb qog nqaij hlav angiogenesis [98], mob qog noj ntshav cell migration [99], thiab qog tiv thaiv kab mob [100]. Galectin-3 tau tshawb pom los khi xaiv rau NKp30 thaum tso tawm ntawm cov qog hlwb, yog li txo NKp30- kho cytotoxicity. Yog li, nws tau tshaj tawm tias cov qog zais zais galectin-3 ua ib qho cuab yeej tshwj xeeb rau kev khiav tawm NKp30-kho NK cell immunosurveillance [101]. Qhov kev xav no yav dhau los tau raug sim hauv vivo, los ntawm kev thaiv Galectin -3 nrog N-acetyllactosamine lossis anti-Galectin -3 antibody kom rov tsim cov IFN los ntawm CTLs [102].
For more information:1950477648nn@gmail.com
