Tumor-infiltrating CD8 ntxiv rau T Cell Antitumor Efficacy Thiab Exhaustion: Molecular Insights Part 1
Jul 05, 2023
Abstract
Kev tiv thaiv tus tswv tsev muaj lub luag haujlwm tseem ceeb hauv kev tswj xyuas cov qog nqaij hlav. Yog li ntawd, nws yog qhov zoo los xaiv cov kev kho mob uas tuaj yeem txhawb cov qog cell tuag thiab ua ke txhawb kev tiv thaiv tus tswv tsev. Lub dynamic qog microenvironment (TME) txiav txim siab seb cov tshuaj antineoplastic yuav ua rau muaj txiaj ntsig zoo lossis cuam tshuam lub cev tiv thaiv kab mob los ntawm qog-infiltrating lymphocytes (TILs). CD8 ntxiv rau T hlwb yog ib qho ntawm thawj cov qog-infiltrating lub cev tiv thaiv kab mob uas xa cov tshuaj tiv thaiv kab mob. Ntawm no, peb tshuaj xyuas qhov cuam tshuam ntawm ntau yam hauv TME ntawm CD8 ntxiv rau T cell qaug zog thiab muaj sia nyob thiab cov tswv yim ua tau los kho CD8 ntxiv rau T cell effector ua haujlwm los ntawm kev siv tshuaj tiv thaiv kab mob.
Txoj kev sib raug zoo ntawm kev qaug zog ntawm tes thiab kev tiv thaiv kab mob yog ze heev.
Cells yog lub hauv paus units uas ua rau peb lub cev, thiab lawv lub xeev vibrant tseem ceeb heev rau peb noj qab haus huv. Txawm li cas los xij, peb cov hlwb ua depleted dhau sijhawm. Qhov no depletion tuaj yeem yog vim muaj ntau yam xws li kev ua qias tuaj ib puag ncig, kev noj zaub mov tsis zoo, thiab kev ntxhov siab.
Thaum cov hlwb depleted, lawv ua tsis muaj zog thiab qaug zog, ua rau peb lub cev tsis muaj zog. Peb lub cev xav tau cov hlwb los tsim cov tshuaj tiv thaiv kab mob los tua cov kab mob thiab cov kab mob uas nkag mus rau peb lub cev. Yog tias peb lub hlwb tsis ua haujlwm zoo, peb lub cev tiv thaiv kab mob yuav ua rau tsis muaj zog thiab raug mob. Qhov no yuav ua rau peb raug ntau yam kab mob, uas yuav cuam tshuam rau peb lub neej thiab kev ua haujlwm.
Txawm li cas los xij, muaj cov kauj ruam uas peb tuaj yeem ua kom qeeb qeeb ntawm peb cov hlwb. Piv txwv li, tswj kev noj zaub mov kom zoo thiab noj cov zaub mov txaus thiab dej; qoj ib ce ntxiv kom muaj lub cev muaj zog; txo kev ntxhov siab kom muaj kev noj qab haus huv lub hlwb.
Tsis tas li ntawd xwb, peb tseem tuaj yeem xaiv siv qee yam tshuaj ntsuab los pab peb lub hlwb kom ciaj sia. Piv txwv li, ntses roj, vitamin D thiab vitamin E, thiab lwm yam.
Hauv ib lo lus, yog tias peb tuaj yeem siv qee yam kev ntsuas kom muaj txiaj ntsig zoo ntawm cov hlwb, ces peb txoj kev tiv thaiv kab mob yuav muaj zog thiab zoo dua tuaj yeem tiv thaiv kev cuam tshuam ntawm ntau yam kab mob thiab kab mob, ua kom peb txoj kev noj qab haus huv thiab kev zoo siab. Nws tuaj yeem pom tias peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho peb txoj kev tiv thaiv. Cov polysaccharides hauv cov nqaij tuaj yeem tswj hwm kev tiv thaiv kab mob ntawm tib neeg lub cev tiv thaiv kab mob, txhim kho kev ntxhov siab ntawm lub cev tiv thaiv kab mob, thiab txhim kho kev tiv thaiv kab mob hauv lub cev. Cov kab mob bactericidal.
Nyem cistanche tubulosa cov txiaj ntsig
Teaser:
Kev kho mob qog noj ntshav cuam tshuam rau qog microenvironment (TME) plasticity thiab hloov CD8 ntxiv rau T cell-mediated antitumor teb. Yog li, kev nkag siab ntawm TME plasticity thiab nws qhov cuam tshuam rau lub cev tiv thaiv kab mob yog qhov tseem ceeb rau kev tsim kho mob qog noj ntshav kom zoo.
Ntsiab lus
qog-infiltrating lymphocytes; CD8 plus T cell; qog microenvironment; immunotherapy; chemotherapeutic agents.
Taw qhia
Kev nkag siab zoo ntawm kev tiv thaiv tus tswv tsev thiab nws lub luag haujlwm hauv kev mob qog noj ntshav yog qhov tseem ceeb rau kev kho mob qog noj ntshav kom zoo. Xav txog qhov tseem ceeb ntawm lub cev tiv thaiv kab mob hauv kev kho mob qog noj ntshav, ntau yam tshuaj tiv thaiv kab mob thiab cov tshuaj tiv thaiv kab mob tau siv los kho ntau yam kab mob malignancies. Cov piv txwv ntawm cov tshuaj immunomodulatory yog cytokines, suav nrog interferons (IFNs), interleukin -2 (IL-2), IL-11, granulocyte-macrophage colony-stimulating factor (GM-CSF), thiab erythropoietin [1]. Cov piv txwv classical ntawm cov tshuaj immunomodulatory hauv kev kho mob yog thalidomide, lenalidomide, thiab pomalidomide [2].
Peb cov tshuaj no ua rau cov cellular tso tawm ntawm IL-2 [2]. Zoo ib yam li cov tshuaj immunomodulating, US Food and Drug Administration (FDA) tau pom zoo cov tshuaj tiv thaiv kab mob tiv thaiv kab mob uas tuaj yeem tsom T cell co-inhibitory molecules, suav nrog cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein. (PD-1), thiab programmed death-ligand 1 (PD-L1).
Cov tshuaj tiv thaiv kab mob no tau ua pov thawj tias muaj txiaj ntsig zoo hauv kev txhim kho T cell-mediated antitumor cuam tshuam hauv ntau yam malignancies, suav nrog melanoma, non-me me cell lung cancer (NSCLC), thiab lwm yam qog nqaij hlav [3]. CTLA-4 thiab PD-1 tswj ob qho tib si peripheral thiab qog-infiltrating T hlwb. Hauv lub cev tiv thaiv kab mob peripheral, CTLA-4 tswj kev loj hlob ntawm T hlwb hauv cov qog ntshav thaum lub sijhawm tiv thaiv kab mob thaum ntxov. Txawm li cas los xij, PD-1 ua haujlwm thaum lub sijhawm tom qab ntawm lub cev tiv thaiv kab mob thiab inhibits T cell function [4]. CTLA-4 yog qhia feem ntau ntawm kev tswj T hlwb (Tregs); nyob rau hauv cov qog, txawm li cas los xij, PD-1 feem ntau yog qhia ntawm T cells [3]. Ntau cov qog qhia PD-L1 thiab cuam tshuam nrog T hlwb qhia PD-1; Qhov kev cuam tshuam no txhawb kev cuam tshuam T cell effector muaj nuj nqi [5].
Cov qog hlwb nyiam tsim ib puag ncig hauv zos protumorigen, tseem hu ua TME. Lub TME encompasses lymphatic thiab cov hlab ntsha, extracellular matrix (ECM), stromal cells (xws li, fibroblasts), lymphocytes, neutrophils, natural killer (NK) hlwb, NK-T hlwb, qog nqaij hlav macrophages (TAMs), RNAs, secreted proteins , thiab me me organelles [6]. Raws li kev muaj lub cev tiv thaiv kab mob, TMEs raug cais raws li kev mob, kev tiv thaiv kab mob tsis paub, lossis kev tiv thaiv kab mob [7]. Raws li qhov muaj thiab tsis muaj T cell infiltrates, qhov mob TME tuaj yeem muab faib ua T cell-inflamed piv rau tsis-T cell-inflamed TME. T-cell-inflamed TME muaj T hlwb thiab lawv cov subsets thiab chemokines [8].
Nws kuj muaj cov macrophages, B hlwb, thiab cov ntshav plasma, qhov uas tsis yog T cell-inflamed TME muaj feem ntau ntawm macrophages [9]. Los ntawm qhov sib txawv, kev tiv thaiv kab mob-tsis paub TME tsis muaj cov cim ua kom pom ntawm T hlwb. Immunological ignorance qhia tau hais tias ib lub xeev uas adaptive lub cev tiv thaiv kab mob tsis muaj peev xwm paub los yog teb rau cov kab mob los yog qog antigens [10]. Lub cev tiv thaiv kab mob-tso suab puam TME yog thaj chaw tiv thaiv kab mob tsis saib xyuas nyob rau hauv cov qog uas tsis muaj kev ua haujlwm zoo T-cell [11].
Lub reprogramming ntawm TME cov neeg nyob ncaj qha los yog tsis ncaj qha cuam tshuam rau lub cev tsis muaj zog thiab stromal hlwb, uas yog li tswj kev loj hlob thiab ciaj sia taus ntawm cov qog nqaij hlav cancer [12]. TME tuaj yeem suav hais tias yog thaj chaw sib ntaus sib tua uas muaj cov kab mob tiv thaiv kab mob thiab cov kab mob tsis muaj zog cuam tshuam nrog cov qog nqaij hlav, thiab ntau tus neeg kho mob soluble, suav nrog ILs, raug tso tawm. qog cell plasticity induces polarization ntawm TME nyob rau hauv ib qho kev tiv thaiv kab mob los yog inflammatory kev taw qhia. Kev tiv thaiv kab mob ntawm TME ua rau txo qis kev tiv thaiv kab mob ntawm tus tswv tsev, ua rau cov qog nqaij hlav thiab mob qog noj ntshav [13]. Qhov tseem ceeb ntawm TME yog piv txwv hauv neuroblastoma, uas feem ntau cuam tshuam rau menyuam yaus.
Txawm hais tias MYCN oncogene hloov pauv hauv ntau tus neeg mob, MYCN-targeted therapy tsis cuam tshuam rau neuroblastoma. Txawm li cas los xij, MYCN kev hloov pauv tsis yog lub luag haujlwm nkaus xwb rau neuroblastoma malignancies; TME kuj tseem muaj txiaj ntsig zoo rau neuroblastoma tumorigenesis, thiab, yog li, cov tswv yim los tsom rau ob lub qog hlwb thiab TME yuav tsum raug txiav txim siab [14,15]. Zoo ib yam li MYCN, c-MYC yog lwm qhov proto-oncogene nrog lub luag haujlwm tseem ceeb hauv kev tswj lub cev tiv thaiv kab mob hauv TME [16]. c-MYC cuam tshuam rau kev tiv thaiv kab mob qog noj ntshav thiab, yog li ntawd, Myc inhibitor, MYCi361, thiab nws cov tshuaj zoo dua qub, MYCi975, tuaj yeem ua rau cov qog nqaij hlav los tiv thaiv PD1 immunotherapy [17]. Nyob rau hauv sib piv rau c-MYC, poob ntawm phosphatase thiab tensin homolog (PTEN) nyob rau hauv cov qog yog txuam nrog ib tug immunosuppressive TME [18]. Zoo ib yam li qhov poob ntawm PTEN, qhov poob ntawm daim siab kinase B1 (LKB1), ib qho serine / threonine kinase, kuj tau tshaj tawm los tswj TME thiab ua rau tsis zoo ntawm cytokine thiab chemokine secretion, suav nrog CCL2, thiab nce kev nrhiav neeg ua haujlwm ntawm protumorigenic macrophages [19 ].
Txoj kev tiv thaiv kab mob tiv thaiv kab mob los ua kom cov qog cell tuag los ntawm cov qog-infiltrating T hlwb, tsom rau cov antigens tshwj xeeb qhia ntawm cov qog hlwb, yog thaj chaw tshiab los kho cov kab mob sib txawv. Cov kev tshawb fawb tsis ntev los no tau pom tias kev qaug zog thiab kev ua haujlwm tsis zoo ntawm T hlwb hauv TME yog txhais cov yam ntxwv ntawm ntau cov qog nqaij hlav. Yog li ntawd, kev nkag siab zoo ntawm cov khoom siv hauv lub cev ntawm T hlwb, xws li lawv cov ciaj sia taus thiab cov txiaj ntsig zoo, yuav yog qhov tseem ceeb rau kev kho cov tshuaj tiv thaiv kab mob tiv thaiv kab mob [20]. Lub xub ntiag ntawm lub cev tiv thaiv kab mob, tshwj xeeb tshaj yog T hlwb hauv TME, txiav txim siab seb cov qog puas kub (T cell inflamed) lossis txias (T cell non-inflamed) [8].
Cov qog kub kub qhia cov tshuaj chemokines, T cell markers, thiab IFN kuv kos npe uas tswj tag nrho cov qog tiv thaiv kab mob [8]. Qhov tseem ceeb ntawm TIL hauv kev tiv thaiv qog nqaij hlav yog qhia los ntawm metastatic melanoma, nyob rau hauv uas T-cell infiltration yog suav tias yog ib tug prognostic biomarker teb rau kev kho. Txawm li cas los xij, kev tsom xam ntawm intertumoral CD8 ntxiv rau T cell suav tau pom tias muaj kev sib txawv rau synchronous thiab metastases. Hauv cov qog synchronous, CD8 ntxiv rau T cell ceev tau muab piv; Txawm li cas los xij, hauv cov qog metachronous, CD8 ntxiv rau T cell ceev yog qhov sib txawv [21]. Cov kev soj ntsuam no qhia tias heterogeneity hauv CD8 ntxiv rau T cell infiltration rau hauv cov qog tswj hwm kev tiv thaiv kab mob sib txawv.
Kev tiv thaiv qog nqaij hlav yog txheej txheem ntau kauj ruam. Thaum lub sij hawm pib, qog hlwb nrog oncogenic mutation (s) qhia cov antigens tshwj xeeb uas cais cov qog nqaij hlav cancer los ntawm cov hlwb noj qab haus huv thiab pab lub cev tiv thaiv kab mob (xws li, antigen-presenting cells; APCs) paub txog cov qog antigens tshwj xeeb. APCs nthuav tawm cov qog antigens rau T hlwb hauv cov qog nqaij hlav, thiab qhov kev cuam tshuam ntawm APCs thiab T hlwb ua rau T cell priming thiab ua kom muaj zog. Cov activated T hlwb migrate thiab infiltrate mus rau hauv lub qog los ntawm kev ncig. Cov qog-infiltrating T hlwb paub txog cov antigen tshwj xeeb ntawm cov qog nqaij hlav cancer thiab thaum kawg ua kom puas. Cov qog nqaij hlav tuag ntxiv tso tawm cov tshuaj tiv thaiv kab mob, uas ua kom cov qog tiv thaiv kab mob [22].
Ntau yam, suav nrog cytokines, kinases, thiab cellular metabolites, tswj kev ciaj sia thiab ua haujlwm ntawm cov qog-infiltrating T hlwb. Hauv kev tshuaj xyuas no, peb tham txog ntau yam TMEderived yam uas cuam tshuam cov qog-infiltrating CD8 ntxiv rau T cell dysfunction thiab xav txog cov tswv yim sib txawv uas tuaj yeem pab kho lawv txoj haujlwm thiab kev ciaj sia los txhim kho kev tiv thaiv kab mob.
Kev nkag mus ntawm CD8 ntxiv rau T hlwb hauv cov qog nqaij hlav
Crosstalk ntawm lub cev tiv thaiv kab mob peripheral thiab TME yog qhov tseem ceeb rau cov lus teb antitumor ntawm effector CD8 ntxiv rau T hlwb. Yog li ntawd, kev nkag siab zoo ntawm peripheral thiab qog-infiltrating T hlwb yog qhov tseem ceeb los ntawm kev saib xyuas kev kho mob. Lub priming, expansion, thiab migration ntawm T hlwb tshwj xeeb rau qog antigens tshwm sim nyob rau hauv lub zos peripheral lymphoid organ, tshwj xeeb tshaj yog nyob rau hauv qog-draining lymph nodes (dLN). dLN-cov neeg nyob hauv T hlwb tau qhib los ntawm cov tshuaj soluble antigens ntawm cov qog, qog nqaij hlav, thiab apoptotic qog hlwb.
Dendritic cells (DCs) tuaj yeem nqa cov qog antigenic peptides los ntawm cov qog mus rau dLN [23]. Thaum lub sijhawm kawg ntawm kev mob qog noj ntshav, CD8 ntxiv rau T hlwb hauv cov qog nqaij hlav ntawm cov qog nqaij hlav nas thiab cov neeg mob poob lawv cov kev ua haujlwm, thaum kawg txo qis cov lus teb antitumor [24]. TILs yog ib qho tseem ceeb thiab tseem ceeb ntawm TME. Cov qog-infiltrating mononuclear lub cev tiv thaiv kab mob ua ib feem tseem ceeb ntawm TILs thiab ua haujlwm ua tus ntsuas kev ua tau zoo ntawm kev siv tshuaj hauv ntau yam qog noj ntshav. TILs muaj lub luag haujlwm tseem ceeb hauv kev tsim cov pro- lossis antitumorigenic TME, cuam tshuam cov qog nqaij hlav thiab kev kho mob tsis zoo [25]. T lymphocytes yog cov khoom tseem ceeb ntawm TILs, uas CD4 ntxiv, CD8 ntxiv, thiab Tregs feem ntau pom nyob rau hauv ntau yam mob qog noj ntshav. CD8 ntxiv rau T hlwb muaj lub luag haujlwm tseem ceeb hauv cov tshuaj tiv thaiv kab mob tiv thaiv kab mob ua ke nrog CD4 ntxiv rau T hlwb. CD8 ntxiv rau T hlwb tso granzyme B, perforin, thiab IFN-, thiab ua raws li cytotoxic hlwb uas thaum kawg tua cov qog nqaij hlav cancer. Kev soj ntsuam ntawm Cancer Genome Atlas (TCGA) cov ntaub ntawv teev siv Oncomine Platform (Thermo Fisher, Ann Arbor, MI, USA) rau CD8 noob qhia hauv malignancies xws li lub hlwb, lub mis, plab hnyuv siab raum (CRC), thiab cov qog zes qe menyuam, qhia tias CD8 noob qhia. yog downregulated nyob rau hauv lub hlwb, CRC, thiab zes qe menyuam qog noj ntshav, tab sis tsis hloov nyob rau hauv mob cancer mis (Daim duab 1a–d).
Txawm li cas los xij, kev txheeb xyuas hauv melanoma thiab mob qog noj ntshav siv TCGA cov ntaub ntawv qhia tias tsis muaj qhov sib txawv loj hauv CD8A daim ntawv luam ntawm cov nqaij mos thiab cov nqaij mos (Daim duab 1e, f). TCGA cov ntaub ntawv teev qhia txog heterogeneity ntawm CD8 noob qhia nyob rau hauv txawv malignancies. Cov qog-nyob CD8 ntxiv rau T hlwb (TILs) feem ntau yog lub cim xeeb T hlwb thiab, yog li ntawd, hu ua cov ntaub so ntswg-nyob nco (TRM) T hlwb. TRM hlwb yog tus cwj pwm los ntawm kev qhia siab ntawm cov cim saum npoo CD103 thiab / lossis CD49a integrins, thiab T cell activation marker, CD69 [26]. Mechanisms ntawm antigen-specific CD8 ntxiv rau T cell ua, nthuav, thiab tsiv mus nyob rau hauv cov qog yog nthuav tawm hauv daim duab 2.
Sib nrug los ntawm TRM T hlwb, muaj ob peb lwm phenotypes ntawm CD8 ntxiv rau T hlwb hauv TME. Qhov tseem ceeb, cov qia zoo li CD8 ntxiv rau T cell phenotype yog suav tias yog qhov tseem ceeb rau cov lus teb antitumor [6]. Stem-zoo li CD8 ntxiv rau T hlwb sib txawv rau hauv effector cytotoxic CD8 ntxiv rau T hlwb thiab nyob hauv cov qog nqaij hlav, qhov twg cov neeg APC muaj ntau [6]. Txawm li cas los xij, muaj qee qhov tsis zoo uas APCs nyob rau hauv cov qog nqaij hlav tsawg thiab sib haum rau txo CD8 ntxiv rau T cell infiltration, ua rau lub cev tsis muaj zog los ntawm cov qog. Yog tias tsis muaj APCs txaus, qhov ua kom CD8 ntxiv rau T hlwb yog qhov cuam tshuam loj heev.
Interestingly, qog-infiltrating CD8 ntxiv rau T hlwb kuj tuaj yeem ua haujlwm los ntawm kev ua kom pom qhov twg T cells qhib rau ib qho antigen tseem tuaj yeem teb tawm tsam cov tsis muaj feem cuam tshuam nrog antigen [27]. Piv txwv li, nyob rau hauv CRC thiab mob ntsws cancer, qog-infiltrating CD8 ntxiv rau T hlwb qhia reactivity nrog qog antigens nrog rau cov antigens tsis txheeb, xws li Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), los yog influenza virus [28]. Lub xub ntiag ntawm tus neeg saib xyuas CD8 ntxiv rau T hlwb hauv cov qog yuav tiv thaiv nws lub cev tiv thaiv kab mob. Qhov tom kawg yog qhov tshwm sim protumor uas ua rau qog cell loj hlob thiab ciaj sia, thiab tsis ua raws li cov lus teb antitumor tshwm sim los ntawm CD8 ntxiv rau T hlwb. Kev txo qis ntawm CD8 ntxiv rau T hlwb kuj tseem tswj hwm los ntawm kev tiv thaiv kab mob tiv thaiv kab mob, kho los ntawm indoleamine-2, 3-dioxygenase (IDO), PD-L1/B7-H1, thiab FoxP3 ntxiv. Cov duab [29]. Kev kho mob qog noj ntshav kuj tseem cuam tshuam cov qog infiltration ntawm CD8 ntxiv rau T hlwb.
Kev kho hluav taws xob ua rau cov hlab ntsha puas tsuaj hauv TME, uas tso cai rau kev nkag mus ntawm TAMs, myeloid-derived suppressor cells (MDSCs), thiab Tregs uas kawg attenuate CD8 ntxiv rau T cell infiltration rau hauv cov qog, inducing immunosuppression [30]. Cov qog-infiltrating CD8 ntxiv rau T hlwb yog prognostically thiab kwv yees tseem ceeb nyob rau hauv lub mis malignancies [31]. Tus nqi kwv yees ntawm TILs yog qhov tshwj xeeb tshaj yog nyob rau hauv triple-negative mis cancers (TNBCs) thiab human epidermal growth factor receptor 2 (HER2 plus) cancers mis [32]. TNBCs yog cov qog nqaij hlav lymphocyte-predominant mis, uas qhia cov pawg ntawm lymphocyte infiltrates [33]. Interestingly, T-cell infiltration rau hauv TNBC qog yog txuam nrog tag nrho cov ciaj sia taus [34]. Txawm li cas los xij, hauv HER2 ntxiv rau mob qog noj ntshav mis, lymphocyte infiltration tsis ncaj qha cuam tshuam nrog kev ciaj sia [35]. Zoo ib yam li TNBCs, nce TILs, thiab txo qis Tregs cuam tshuam nrog kev txhim kho txoj sia nyob hauv cov neeg mob qog noj ntshav zes qe menyuam [36]. Tsis zoo li TNBC, pancreatic ductal adenocarcinoma (PDAC) tsis muaj cov qog nqaij hlav infiltration ntawm CD8 ntxiv rau T hlwb; Txawm li cas los xij, PDAC TME yog dej nyab nrog cov kab mob inflammatory. Hauv PDAC, muaj cov kab mob inflammatory infiltrates hauv TME accelerates qog loj hlob thiab metastasis thiab suppresses lub zog ua haujlwm ntawm cytotoxic CD8 ntxiv rau T hlwb [37]. \
Cov piv txwv no qhia tias cov qog-infiltrating CD8 ntxiv rau T hlwb muaj lub luag haujlwm tseem ceeb hauv cov qog regression thiab tag nrho cov ciaj sia. Txawm li cas los xij, heterogeneous infiltration ntawm CD8 ntxiv rau T hlwb rau hauv cov qog tseem tsis meej nyob rau hauv cov qog sib txawv. Qhov kev faib tawm no tuaj yeem tswj hwm los ntawm ntau yam, suav nrog cytokine milieu hauv TME, cov xwm txheej ntawm cov protein kinases, thiab kev hloov pauv ntawm cov txheej txheem metabolic.
Cytokines thiab lawv lub luag haujlwm hauv CD8 ntxiv rau T cell infiltration rau hauv qog
Cytokines yog ib pab pawg me me secretory proteins uas ua los ntawm ntau hom hlwb, nrog rau lub cev tsis muaj zog thiab qog hlwb. Cytokines yog cov tswj hwm tseem ceeb ntawm TME plasticity thiab muaj lub luag haujlwm tseem ceeb hauv CD8 ntxiv rau T cell infiltration thiab effector muaj nuj nqi (Table 1). IL-2 tswj CD8 ntxiv rau T cell activation thiab proliferation thiab induces CD8 ntxiv rau T cell-mediated anti-tumor teb [38].
Nws kuj ua ke nrog IL-12 thiab IFN- hauv augmenting cytotoxic muaj nuj nqi ntawm qog-infiltrating CD8 ntxiv rau T hlwb [39]. Nyob rau hauv sib piv rau cov cytokines no, ob peb lwm cytokines, xws li IL-10 thiab IL-35, suppress lub antitumor muaj nuj nqi ntawm qog-infiltrating CD8 ntxiv rau T hlwb [40]. IL-10 yog ib qho tshuaj tiv thaiv kab mob cytokine uas cuam tshuam rau CD8 ntxiv rau T cell qog reactivation feem ntau ntawm tempering IFN- ntau lawm [41]. IL-10 thiab IL-35 raug tso tawm los ntawm Tregs thiab upregulate co-inhibitory proteins, xws li PD-1, PD-L1, thiab CTLA-4 qhia ntawm qog-infiltrating CD8 ntxiv rau T cell. T cell co-inhibitory molecules txhawb kev ua haujlwm tsis zoo hauv T cell activation, expansion, effector function, thiab ciaj sia taus. Kev sib koom ua ke ntawm IL-10 thiab IL-35 co-inhibitory proteins inhibits lub zog ua haujlwm thiab ua rau qaug zog hauv qog-infiltrating CD8 ntxiv rau T hlwb [40]. Ntxiv rau kev tso tawm IL-10 thiab IL-35, Tregs kuj cuam tshuam nrog CD11c ntxiv rau DCs thiab txo qis kev ua kom thiab nthuav dav ntawm CD8 ntxiv rau T hlwb hauv cov qog. Cov kev tshawb fawb tsis ntev los no tau pom tias qhov depletion ntawm Tregs hauv PDAC ua rau muaj kev cuam tshuam ntawm IFN- - ua cytotoxic CD8 ntxiv rau T hlwb rau hauv cov qog [42]. Lwm qhov tseem ceeb cytokine, hloov pauv qhov kev loj hlob-beta (TGF- ), kuj tau tshaj tawm tias muaj lub luag haujlwm hauv qog loj hlob / ciaj sia thiab tiv thaiv tus tswv tsev. TGF- induces immunosuppression nyob rau hauv tus tswv tsev thiab pab cov qog khiav tawm ntawm lub cev tiv thaiv kab mob [43]. Yog li, nws tau raug tshaj tawm tias TGF- attenuation txhawb CD8 ntxiv rau T cell-mediated antitumor teb [43].
Ib yam li ntawd, ib txoj kev tshawb fawb hauv murine qauv ntawm PDAC tau pom tias kev hloov pauv ntawm TGF -insensitive CD8 ntxiv rau T hlwb induced qog regression [44]. IL-4 thiab IL-12 zoo ib yam cuam tshuam rau CD8 ntxiv rau T cell effector ua haujlwm tsis zoo los ntawm kev cuam tshuam qhov nthuav dav ntawm CD8 ntxiv rau Tregs nrog Foxp3−IL-10 ntxiv rau phenotype [45]. Tumor necrosis factor alpha (TNF-) tso tawm los ntawm cov qog nqaij hlav cancer thiab stromal hlwb tau tshaj tawm tias yuav ua rau apoptosis hauv qog-infiltrating CD8 ntxiv rau T hlwb [46].
Nrog rau cov tshuaj tiv thaiv kab mob cytokines, hauv TME, cov tshuaj tiv thaiv kab mob cytokines tam sim no uas pab kho cytotoxic CD8 ntxiv rau T cell muaj nuj nqi. Lub pleiotropic cytokine, IL-15, yog secreted los ntawm ntau yam kev tiv thaiv kab mob thiab tsis muaj kab mob ntawm tes thiab yog txuam nrog o thiab tiv thaiv kab mob [47]. IL-15 induces NK, NK-T, thiab cytotoxic CD8 ntxiv rau T hlwb, thiab suav hais tias yog ib tus neeg muaj peev xwm los kho mob qog noj ntshav [48]. Lub luag haujlwm ntawm IL-15 hauv kev txhawb nqa cov lus teb antitumor tau tshwm sim hauv kev mob qog noj ntshav ntawm zes qe menyuam. Ovarian qog antigen-loaded ntawm cytokine-matured human DCs, nrog rau kev sib xyaw ntawm IL-15 thiab p38 inhibitor, induced CD4 plus Th17- cov lus teb kho mob thiab CD8 ntxiv rau T cell cytotoxicity [49].
Th17 pab hlwb yog ib pawg ntawm CD4 ntxiv rau T hlwb uas tso tawm cov proinflammatory cytokine, IL-17, uas kuj ua rau muaj kev tiv thaiv kab mob. Hauv tus qauv mob qog noj ntshav zes qe menyuam, IL-17 hauv TME induced antitumor immune responses [49]. IL-18, tseem hu ua IFN- -inducing factor (IGIF), yog ib qho antitumor cytokine thiab txhawb nqa T cell ua kom [50]. Hauv cov qauv qog nqaij hlav syngeneic thiab humanized, qhov blockade ntawm ectoenzyme CD39 induced tso tawm active IL-18 thiab prompted expansion ntawm qog-infiltrating CD8 ntxiv rau effector T hlwb [51]. Yog li ntawd, muaj kev txaus siab loj hlob hauv kev txheeb xyuas cytokines hauv TME kom nkag siab txog lawv txoj haujlwm hauv kev tswj cov qog-infiltrating CD8 ntxiv rau T hlwb thiab uas tuaj yeem siv los hloov TME dynamics los kho cov tshuaj tiv thaiv kab mob ntawm CD8 ntxiv rau T hlwb.
Me-molecular-yuag cytokines, tseem hu ua chemokines, muaj lub luag haujlwm tswj hwm hauv T-cell tsiv teb tsaws. Effector T cell tsiv teb tsaws yog ib kauj ruam tseem ceeb uas yuav tsum tau ua rau cov lus teb antitumor. Chemokines tswj kev nkag mus ntawm T hlwb hauv TME. Kev koom tes ntawm T cell infiltration thiab chemokine receptor CXCR3 thiab ligands CXCL9, CXCL10, thiab CXCL11 hauv kev nrhiav CD8 ntxiv rau T hlwb, Th1 hlwb, thiab NK hlwb tau tshaj tawm hauv cov qog [52]. Chemokines qhia nyob rau hauv melanomas muaj xws li CCL2, CCL3, CCL4, CCL5, CCL19, CCL21, CXCL9, CXCL10, CXCL11, thiab CXCL13, thiab yog txuam nrog infiltration ntawm lymphocytes [53]. Interestingly, CD8 transcript qhia yog nruj me ntsis txuam nrog ntau dua qhia ntawm CCL2, CCL4, CCL5, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13, thiab XCL2 nyob rau hauv lymphocytes infiltrating melanoma hlav [53].
Muab lub luag haujlwm tseem ceeb ntawm cytokines / chemokines hauv kev tswj cov lus teb antitumor ntawm CD8 ntxiv rau T hlwb, cytokine-raws li kev kho mob tau siv rau ntau yam qog noj ntshav. Ib qho ntawm thawj cytokine-raws li kev kho mob qog noj ntshav yog IL-2-raws li kev kho mob. Systemic IL-2 kev kho mob tau siv los ua kom muaj kev tiv thaiv kab mob tiv thaiv kab mob hauv metastatic melanoma thiab mob qog noj ntshav raum; Txawm li cas los xij, kev kho mob IL-2 (piv txwv li, aldesleukin) kev kho mob yog txuam nrog toxicity [54]. Txawm li cas los xij, cov koob tshuaj qis IL-2-derivative PEGylated IL-2 (ie, NKTR-214) tau pom tias muaj txiaj ntsig zoo los tiv thaiv qog noj ntshav nrog cov tshuaj toxicity txaus [54]. Cov txiaj ntsig tau tshwm sim no qhia txog kev cog lus kho mob yav tom ntej rau kev kho mob qog noj ntshav cytokine los txhim kho T cell-mediated antitumor teebmeem.
Immunotherapeutics rau potentiate qog-infiltrating CD8 ntxiv rau T hlwb
Cov kev tshawb fawb tseem ceeb tau tsom mus rau kev nrhiav cov tshuaj tiv thaiv kab mob kom nce thiab kho cov haujlwm ntawm cov qog-infiltrating CD8 ntxiv rau T hlwb rau kev kho mob qog noj ntshav. CD8 ntxiv rau T cell dysfunction feem ntau tshwm sim hauv cov qog nqaij hlav thiab, yog li ntawd, ntau txoj hauv kev tau pom zoo kom nce CD8 ntxiv rau T cell infiltration thiab rov ua nws txoj haujlwm. Qee txoj hauv kev sim suav nrog kev siv tshuaj kho cov tshuaj tiv thaiv kab mob (CPI) cov tshuaj tiv thaiv, T cell co-stimulatory molecules, agonistic antibodies, chimeric antigen receptor (CAR)-T hlwb, TCR-transduced T hlwb, thiab TIL-raws li kev kho mob qog noj ntshav ( Daim duab 3).
Targeting T cell co-inhibitory axis rau kev kho mob qog noj ntshav
Kev qhia ntawm T cell co-inhibitory molecules (PD1, PD-L1, thiab CTLA-4) tau tshaj tawm kom txo qis T cell ua kom muaj zog, ua haujlwm, thiab muaj sia nyob. Qhov tseem ceeb, thaiv ntawm cov coinhibitory molecules reprograms T cell ua haujlwm hauv ntau cov qog nqaij hlav [55]. Txawm li cas los xij, qhov kev thaiv no tau pom tias muaj txiaj ntsig zoo rau qee hom hematological thiab mob qog noj ntshav.
T cell co-inhibitory molecules, CTLA-4, thiab PD1, yog cov tswj hwm tseem ceeb ntawm nruab nrab thiab peripheral kam rau ua. T cell progenitors pib los ntawm cov pob txha pob txha thiab kev loj hlob nyob rau hauv lub thymus, qhov uas tsis paub tab T hlwb proliferate thiab tsim ib tug ntau yam ntawm TCRs vim hais tias ntawm recombination ntawm TCR noob ntu [56]. Cov T hlwb uas tuaj yeem khi rau tus kheej-antigens raug tshem tawm los tiv thaiv autoreactivity los ntawm cov txheej txheem hu ua 'central tolerance'. Txawm hais tias qhov no muaj txiaj ntsig zoo los tiv thaiv autoimmune reactivity, nws tsis haum rau cov lus teb anticancer [57]. CTLA-4 koom nrog hauv nruab nrab kam rau ua thiab, thaum lub sij hawm T cell txoj kev loj hlob, CTLA-4 tswj effector thiab regulatory T hlwb [58]. Ib qho ntawm cov txheej txheem uas CTLA-4 tswj T cell kam rau ua yog los ntawm kev nce T cell ua kom pib. Qhov tsawg kawg nkaus lub cev tiv thaiv kab mob uas tshwm sim los ntawm kev nce qib ntawm T hlwb tiv thaiv tus kheej-peptide (s) yog qhov zoo rau kev tiv thaiv tus tswv [58]. Txawm li cas los xij, CTLA-4 muaj nuj nqi yog qhov tseem ceeb rau T cell homeostasis thiab, yog li ntawd, kev pom zoo ntawm CTLA{13}} yog qhov tseem ceeb rau cov txiaj ntsig kho tau zoo. Kev poob caj ces ntawm CTLA-4 induces uncontrolled T-cell proliferation, ua rau muaj teeb meem kev noj qab haus huv thiab txawm tuag [59].
Lwm T cell co-inhibitory axis, PD1 / PD-L1, kuj tseem cuam tshuam nrog kev tswj hwm ntawm lub hauv paus kam rau ua. Cov axis no tswj kev hloov ntawm thymocytes los ntawm thymic ob qhov tsis zoo (DN) mus rau theem ob-zoo (CD4 ntxiv rau CD8 ntxiv) ntawm T hlwb. Qhov kev hloov pauv no tau txhawb nqa los ntawm kev poob ntawm PD-1, qhia tias PD-1 koom nrog kev tswj hwm ntawm T cell repertoire [60]. Naïve T hlwb tso tawm los ntawm thymus mus rau peripheral, spleen thiab lymphoid organ cuam tshuam nrog APCs, nthuav tawm txawv teb chaws antigenic peptide (s) los yog qog antigen(s). Qee zaum, tsis muaj T cells hnov qab tiv thaiv tus kheej-peptides vim qee qhov TCRs paub txog tus kheej cov protein [61]. Txhawm rau tiv thaiv xws li T cell autoreactivity, ob peb co-inhibitory molecules inhibit T cell activation, hu ua peripheral kam rau ua [62]. Cov co-inhibitory molecules no, suav nrog CTLA-4 thiab PD-1, tswj T-cell ua rau ntau theem. CTLA{19}} thiab PD-1 sib txawv tswj CD4 ntxiv thiab CD8 ntxiv rau T cell phenotypes, ntsig txog [59]. CTLA-4 tswj T cell activation thaum ntxov nyob rau hauv cov ntaub so ntswg lymphoid, whereas PD-1 tswj T cell activation ntawm lig activation theem nyob rau hauv peripheral cov ntaub so ntswg [63].
Ib qho ntawm cov txheej txheem ntawm kev tiv thaiv kab mob peripheral tau tshaj tawm los ntawm kev sib cuam tshuam ntawm PD-L1 ntawm APCs thiab PD-1 ntawm T hlwb uas ua rau T cell tiv thaiv kab mob tiv thaiv tus kheej-antigen [64]. Lwm cov txheej txheem tiv thaiv kab mob peripheral suav nrog T cell qaug zog thiab nce hauv Treg cell pejxeem [65]. Kev kho mob nrog cov tshuaj tiv thaiv CTLA-4 cov tshuaj tiv thaiv kab mob hauv cov qauv qog pom tias ua kom muaj zog T cell ua haujlwm, txhawb nqa Treg depletion, thiab txhim kho cov tshuaj tiv thaiv kab mob tiv thaiv kab mob thiab cov qog regression [66,67]. Txawm hais tias CTLA{10}} depletes Tregs hauv TME, anti-CTLA{12}} tsis cuam tshuam nrog Treg depletion hauv cov kab ke peripheral. Lub peripheral depletion ntawm Tregs kuj muaj feem xyuam nrog lub xub ntiag ntawm Fc receptor nyob rau hauv lub host cells. Yog li, qhov ua tau zoo ntawm kev tiv thaiv CTLA-4 antibody-based immunotherapy hauv cov qog nqaij hlav tuaj yeem nyob ntawm Fc gamma receptor (Fc R) khi [68]. Xav txog qhov sib txawv ntawm kev tswj hwm lub luag haujlwm ntawm PD-1 thiab CTLA{18}} hauv kev tiv thaiv kev tiv thaiv kab mob, lawv cov blockade tau pom zoo los muab cov lus teb tseem ceeb los ntawm kev ua kom cov effector: suppressor immune cell ratio [69].
Qhov thaiv ntawm PD-1/PD-L1 T cell co-inhibitory axis tau raug tsom los txhim kho CD8 ntxiv rau T cell infiltration rau hauv cov qog thiab kho cov tshuaj tiv thaiv kab mob tiv thaiv kab mob [70]. PD-1 sib txawv cuam tshuam rau CD8 ntxiv rau T cell effector muaj nuj nqi hauv ntau hom mob qog noj ntshav [71–74]. Piv txwv li, hauv qee hom mob qog noj ntshav mis, tsis hais txog PD-1 kev qhia ntawm CD8 ntxiv rau T hlwb, cov nyhuv effector tsis hloov pauv [74]. Los ntawm qhov sib txawv, hauv melanoma, muaj PD-1 ntawm CD8 ntxiv rau T hlwb txo qis T cell effector function [75,76]. Ib yam li ntawd, qhov thaiv ntawm lwm T cell co-inhibitory molecule, CTLA-4, txhawb cov qog regression los ntawm kev rov ua haujlwm cytotoxic ntawm qog-infiltrating CD8 ntxiv rau T hlwb hauv ntau cov qog nqaij hlav [77,78]. Hauv CT26 mob qog noj ntshav thiab ID8-VEGF ntawm zes qe menyuam qog noj ntshav tsiaj qauv, PD-1 tau qhia txog lub luag haujlwm tswj hwm hauv Foxp3 ntxiv rau Treg thiab CD8 ntxiv rau T cell muaj nuj nqi, qhov nce CTLA-4 qhia tau cuam tshuam nrog Kev ua haujlwm tsis zoo ntawm CD8 ntxiv rau T effector hlwb. CD8 ntxiv rau T cell dysfunctions, tshwj xeeb tshaj yog lawv proliferation thiab cov cuab yeej tso tawm cytokines, tau hnyav heev hampered nyob rau hauv PD-1 ntxiv rau CTLA-4 ntxiv rau CD8 ntxiv rau T hlwb piv nrog rau PD-1 ntxiv rau CD8 ntxiv. los yog CTLA4 plus CD8 plus T cells.
Cov txiaj ntsig no qhia tias kev sib xyaw ua ke ntawm PD-1 thiab CTLA-4 ntawm CD8 ntxiv rau T hlwb cuam tshuam rau CD8 ntxiv rau T cell-mediated antitumor tiv thaiv kab mob thaum lub sijhawm kho mob qog noj ntshav [78]. Cov tswv cuab ntawm lub cev tiv thaiv kab mob hauv lub cev, DCs thiab NK hlwb, thiab cov tswv cuab ntawm lub cev tiv thaiv kab mob, T pab hlwb (CD4 ntxiv rau T cell subset), pab txhawb cov priming ntawm CD8 ntxiv rau T hlwb rau cov qog antigen. PD-1 thiab CTLA-4 txwv tsis pub CD8 ntxiv rau T cell priming thiab, yog li, ua rau kom qaug zog ntawm cov qog-infiltrating CD8 ntxiv rau T hlwb [79]. Tsis tas li ntawd, PD-1 thiab CTLA{15}} tuaj yeem sib tham nrog lwm cov proteins kom ua rau CD8 ntxiv rau T hlwb ua haujlwm tsis zoo. Vascular endothelial growth factor (VEGF) thiab semaphorin receptor, neuropilin-1 (Nrp-1), yog overexpressed ntawm qog-infiltrating CD8 ntxiv rau T hlwb thiab, ua ke nrog PD-1 lossis CTLA{{ 22}}, cuam tshuam T cell functions [80]. Hauv tib neeg lub ntsws cancer, Nrp-1 muaj nyob rau hauv CD8 ntxiv rau PD-1 ntxiv cov hlwb (ie, Nrp1 ntxiv rau PD-1 ntxiv rau CD8 ntxiv rau T cells) thiab cuam tshuam nrog semaphorin 3A ntawm cov qog hlwb. Kev cuam tshuam ntawm Nrp-1 nrog semaphorin 3A ua rau txo qis ntawm CD8 ntxiv rau T cell migration thiab cytotoxicity. Hauv B16F10 melanoma qauv, CD8 ntxiv rau T hlwb, qhia Nrp1 thiab PD-1 (ie, Nrp1 plus PD-1 plus CD8 plus ) muaj nyob rau hauv cov qog thiab nthuav tawm lub xeev qaug zog, raws li pov thawj los ntawm elevated. expression of LAG-3, Tim-3, and CTLA-4 [80].
Lub infiltration ntawm CD8 ntxiv rau T hlwb rau hauv cov qog kuj yog tswj los ntawm WNT / -catenin signaling. Hauv tib neeg metastatic melanomas, upregulation ntawm intrinsic WNT / -catenin signaling yog txuam nrog qhov tsis muaj T cell gene kos npe [81]. Ib yam li ntawd, nyob rau hauv tus qauv autochthonous nas melanoma, nce qog-intrinsic WNT/ -catenin signaling induced T cell depletion thiab tiv thaiv anti-PD-1 lossis anti-CTLA-4 kho [81].
Qhov thaiv ntawm PD-1 tau pom tias muaj kev ua tau zoo hauv tsev kho mob rau qee yam mob qog noj ntshav. Yog li ntawd, nkag siab tag nrho cov txheej txheem molecular sib kho los ntawm cov chaw kuaj xyuas yuav tso cai rau cov tswv yim tshiab los tsim kho CD8 ntxiv rau T cell functions. Yog li, lwm cov tshuaj pharmacological tau siv los ua kom muaj txiaj ntsig zoo ntawm cov tshuaj tiv thaiv kab mob. Piv txwv li, PD-1 blockade ib leeg hauv CT26 nyuv qog noj ntshav, TSA mammary adenocarcinoma, thiab MCA38 nyuv qog noj ntshav nas qauv tsis qhia cov txiaj ntsig kho mob tseem ceeb. Txawm li cas los xij, kev kho mob sib xyaw ua ke ntawm PD-1 thiab kev txhaj tshuaj intratumoral ntawm kev sib cuam tshuam zoo li tus neeg hu xov tooj 9 (TLR9) agonist, SD101, tau pom cov tshuaj tiv thaiv kab mob los ntawm intratumoral CD8 ntxiv rau T hlwb [82]. Hauv tus qauv nas mob qog noj ntshav, TGF- hauv TME cuam tshuam kev ua haujlwm ntawm kev sib xyaw ua ke ntawm gemcitabine thiab anti-PD-1. Txawm li cas los xij, qhov kev kho mob sib xyaw ua ke no ua rau muaj kev sib koom ua ke ntawm cytotoxic CD8 ntxiv rau T hlwb thiab txo cov qog nqaij hlav thaum TGF- raug thaiv [83]. US Food and Drug Administration (FDA) tau pom zoo inhibitory antibodies tiv thaiv CTLA-4 (ie, Ipilimumab), PD1 (ie, nivolumab, pembrolizumab, thiab ceiplimab), thiab PD-L1 (ie, atezolizumab, nivolumab, thiab duvalumab). Table 2 muab piv txwv ntawm kev sim tshuaj rau cov qog nqaij hlav, tsom rau T cell co-inhibitory lossis co-stimulatory proteins.
T cell qaug zog yog qhov tsis ua haujlwm lossis tshem tawm lub cev ntawm T hlwb hauv cov lus teb rau cov tshuaj tiv thaiv tshwj xeeb thaum muaj kab mob ntev, suav nrog kev kis kab mob thiab mob qog noj ntshav [84]. T hlwb ua rau qaug zog poob lawv lub peev xwm loj hlob thiab ua haujlwm ua haujlwm, thiab lawv lub cim xeeb rov qab raug cuam tshuam [85]. Cov T hlwb uas ploj lawm yog tus cwj pwm los ntawm kev nthuav tawm ntawm co-inhibitory receptors, suav nrog PD-1, CTLA-4, lymphocyte activation gene-3 (LAG3; CD223), T cell immunoglobulin thiab mucin domain{ {8}} (TIM-3), CD39, CD96, CD160, T cell immunoreceptor nrog Ig thiab ITIM domains (TIGIT), 2B4 (CD244), thiab B thiab T lymphocyte attenuator (BTLA) [85].
Kev siv tshuaj tiv thaiv kab mob ntawm cov tshuaj tiv thaiv kab mob ntawm PD-1 thiab lwm cov molecules tuaj yeem rov ua kom cov T cell uas tsis muaj zog thiab muab cov txiaj ntsig kho mob rau cov neeg mob uas muaj ntau yam malignancies (Table 3) [86–107]. Hmoov tsis zoo, cov txiaj ntsig ntawm PD1-raws li qhov chaw kuaj xyuas tsis zoo rau txhua tus neeg mob, thiab T cell qaug zog tsis yog ib txwm thim rov qab rau cov neeg mob uas muaj mob hnyav heev [108]. Tsis ntev los no, qog-reactive TILs tau tshaj tawm tias muaj cov cim qhia ntawm lub cev sab hauv thiab lub cim xeeb nrog rau kev qhia ntawm PD-1 thiab T cell factor 1 (Tcf1). PD1 ntxiv rau TCf1 ntxiv rau TILs yog txuam nrog kev tiv thaiv kab mob tiv thaiv kev loj hlob [109]. Hauv qee cov neeg mob qog noj ntshav, kev qhia ntawm PD-1 yog siab dua ntawm kev ua haujlwm thiab ua haujlwm CD8 ntxiv rau T hlwb. Yog li ntawd, anti-PD1 antibody-based immunotherapy tsis zoo rau cov neeg mob no kom rov muaj zog T hlwb [110].
Ib yam li ntawd, kev tshawb fawb hauv cov qauv qog nqaij hlav syngeneic pom tau tias PD1 blockade-based immunotherapy tsis tuaj yeem rov qab ua haujlwm tsis zoo PD-1 ntxiv rau CD38 ntxiv rau CD8 ntxiv rau T hlwb [111]. Qhov tsis ua hauj lwm ntawm kev kuaj xyuas blockade-raws li kev tiv thaiv kab mob kom rov ua kom lub hlwb T hlwb tuaj yeem cuam tshuam nrog cov txheej txheem sab hauv thiab sab nrauv ntawm kev tiv thaiv. Cov txheej txheem ntawm T cell qaug zog yog sib txawv ntawm cov qog nqaij hlav sib txawv. Piv txwv li, ib txoj kev tshawb fawb hauv melanoma (B16F10), lub mis (E0771), thiab kab mob ntsws ntsws (LLC) xovtooj ntawm tes qhia tias txhua tus qog muaj tus yam ntxwv thiab qhov txawv ntawm TIL qaug zog kos npe [88].
Raws li kev ua ntej ntawm T cell qaug zog thiab rov ua kom lub cev muaj zog, qhov kev ntsuam xyuas lub cev muaj txiaj ntsig zoo los ntawm kev txheeb xyuas cov modulators ntawm T cell qaug zog tau raug tshaj tawm uas tuaj yeem siv los tshuaj xyuas cov khoom me me uas tuaj yeem thim rov qab T cell sab hauv tus kab mob lymphocytic choriomeningitis. Qauv (LCMV) [112]. Nws ntseeg tau tias txoj hauv kev muaj txiaj ntsig zoo siv kev sib xyaw ua ke ntawm me me-molecule thiab checkpoint inhibitors tuaj yeem siv los rov ua kom cov CD8 ntxiv rau T hlwb hauv kev kho mob qog noj ntshav.
Targeting T cell co-stimulatory axis hauv kev kho mob qog noj ntshav
Ntxiv nrog rau kev sim tshuaj nrog cov tshuaj tiv thaiv PD-1 thiab cov tshuaj tiv thaiv CTLA-4, lwm yam kev sim tsom rau T cell co-stimulatory proteins tseem tab tom ua (Table 2). Piv txwv ntawm T-cell co-stimulatory molecules uas tuaj yeem raug tsom los kho T-cell muaj nuj nqi yog 4-1BB, OX40, CD40, CD27, CD70, inducible T-cell co-stimulator (ICOS), thiab glucocorticoid-induced qog necrosis factor receptor-related protein (GITR) [113–115]. Kev ua kom ntawm 4-1BB, ib tus neeg hauv tsev neeg TNFR, nce cytotoxicity ntawm CD8 ntxiv rau T hlwb ntawm induction ntawm IFN- [116]. Kev sim tshuaj nrog cov tshuaj agonistic monoclonal antibodies (mAbs) utomilumab (PF-05082566) thiab sarilumab (BMS{25}}) uas ua kom 4-1BB tseem ua rau ntau yam qog noj ntshav [117]. Txawm hais tias kev sim tshuaj ntsuam xyuas tau pom tias muaj cov lus teb los tiv thaiv qog nqaij hlav, muaj kev cuam tshuam loj heev kuj tau pom vim tias Fc R cuam tshuam nrog cov hom phiaj tsis tshwj xeeb.
Txhawm rau txo / kov yeej qhov tsis txaus siab toxicity ntawm 4-1BB agonistic mAbs, Fc-dawb qog-targeted 4-1BB-agonistic antibody tau siv uas xa cov txiaj ntsig kho tau zoo dua [118]. OX40 yog lwm T cell co-stimulatory molecule nyob rau saum npoo ntawm T cells activated. Kev sib cuam tshuam ntawm OX40 thiab nws ligand, OX40L, txhawb nqa T cell expansion thiab Treg tsub kom nce antitumor teb [119]. Muab lub luag haujlwm tseem ceeb ntawm OX40 hauv kev tswj hwm ntawm CD8 ntxiv rau T cell effector muaj nuj nqi, kev tiv thaiv OX40 agonistic mAb yog nyob rau hauv kev sim tshuaj kho mob qog noj ntshav. 4-1BB thiab OX40 agonistic mAbs kuj tau tshwm sim los kho MEK inhibitor-induced T-cell dysfunction [120]. Lwm T cell co-stimulatory axis, CD40LCD40, kuj tau tshaj tawm los txhawb MEK inhibitor-induced cancer cell tuag hauv cov qauv tsiaj. Nyob rau hauv cov mutant KRas-tsav pancreatic cancer tsiaj qauv, kev sib xyaw ua ke ntawm MEK inhibitor thiab agonistic anti-CD40 mAb tau pom cov lus teb muaj zog tiv thaiv kab mob [121]. CD27-CD70 axis kuj tseem ceeb hauv kev ua kom T cell, thiab kev nthuav qhia ntau ntxiv ntawm CD70 thiab CD27 tau tshaj tawm ob qho tib si hauv cov qog nqaij hlav hematological thiab tawv nqaij [113,122].
Hauv papillary thyroid cancer, CD70 qhia tau kuaj pom ntawm cov qog hlwb, qhov kev qhia ntawm CD70 receptor, CD27, feem ntau yog nyob rau hauv intratumoral lymphocytes [123]. GITR yog lwm co-stimulatory molecule uas koom nrog hauv T cell ua. Kev sib xyaw inhibition ntawm PD-1 thiab GITR synergistically nce T cell qog infiltration thiab ruaj khov los tiv thaiv qog los ntawm CD8 ntxiv rau T hlwb [124]. ICOS yog ib qho ntxiv co-stimulatory molecule tam sim no nyob rau hauv activated T hlwb thiab kuj tau tsom rau mob qog noj ntshav [125]. Interestingly, kev siv ua ke ntawm ICOS aptamer thiab CTLA -4 inhibition pom tau tias muaj zog antitumor teb los ntawm cytotoxic T hlwb [126]. Muab qhov tseem ceeb ntawm T cell co-stimulatory molecules hauv kev tiv thaiv kab mob qog noj ntshav, kev tshawb fawb txog kev tiv thaiv kab mob tam sim no tau tsom mus rau kev nrhiav cov tshuaj tshiab los ua rau T cell co-stimulatory txoj hauv kev.
Ntau qhov kev tshawb fawb preclinical thiab kev sim tshuaj ntsuam xyuas tab tom sim kuaj cov kev kho mob ntawm co-inhibitory lossis costimulatory immune receptors. Txawm li cas los xij, tam sim no FDA tau pom zoo tsuas yog tshuaj tiv thaiv PD1 / PD-L1 thiab tshuaj tiv thaiv CTLA-4 tshuaj tiv thaiv kab mob qog noj ntshav rau kev siv tshuaj kho mob hauv qee qhov mob qog noj ntshav. Feem ntau ntawm cov kab mob immunotherapeutic uas tsom rau cov costimulatory molecules tseem tsis tau pom zoo los ntawm kev kho mob. Tej zaum yuav muaj ntau yam laj thawj rau kev siv ncua sijhawm ntawm cov tshuaj tiv thaiv kab mob agonistic hauv cov chaw kho mob, suav nrog cov tshuaj tiv thaiv kab mob bivalent thiab co-stimulatory molecules ntawm Tregs [127].
Nyob rau hauv cov tshuaj bivalent antibody hom, qhov sib txawv Fc gamma receptors (Fc R) yog ib qho kev txhawj xeeb loj. Fc R tswj cov tshuaj tiv thaiv kab mob ua kom muaj zog ntawm effector T hlwb thiab cov tshuaj tiv thaiv kab mob [127]. Ua piv txwv, ua kom tiav cov kev ua haujlwm antitumor ntawm 4-1BB agonistic antibody yuav tsum tau Fc R-dependent Treg depletion thiab Fc R- ywj siab 4-1BB agonism [128]. Ib qho ntawm cov laj thawj tseem ceeb rau qhov tsis ua tiav ntawm cov tshuaj tiv thaiv agonistic tiv thaiv co-stimulatory molecules yog tias Tregs nthuav qhia ntau co-stimulatory molecules [128]. Conceivably, co-stimulatory agonistic cov tshuaj tiv thaiv yuav ua pov thawj ib qho kev kho mob zoo hauv kev mob qog noj ntshav; Txawm li cas los xij, kev nkag siab zoo txog kev siv tshuab yuav tsim nyog rau lawv daim ntawv thov kho mob.
CAR-T cell kho mob cancer
Kev saws me nyuam ntawm cov tshuab T hlwb tau pom cov txiaj ntsig kho mob rau qee cov neeg mob qog noj ntshav. Hauv kev mob qog noj ntshav hematological, kev hloov pauv ntawm cytotoxic lymphocytes tsom cov qog hlwb tau ua tiav [129]. TCRs tuaj yeem siv los txhim kho lawv txoj sia nyob thiab ua haujlwm zoo. Yog li ntawd, CAR-T hlwb muaj qhov tshwj xeeb tiv thaiv qog nqaij hlav antigens tau tsim thiab pom tau tias muaj txiaj ntsig zoo hauv cov qog nqaij hlav hematological. Txawm li cas los xij, CAR-T hlwb los kho cov qog nqaij hlav tawv tseem nyob rau theem pib, tsis muaj kev vam meej txog tam sim no. Lub hauv paus yog vim li cas rau lawv tsis ua hauj lwm tawm tsam cov qog nqaij hlav yog tias qhov chaw tiv thaiv kab mob hauv TME nyiam cov qog loj hlob los ntawm kev txhawb nqa CD8 ntxiv rau T cell tsis ua haujlwm. CAR-T hlwb hauv TME raug thawb los ua tsis ua haujlwm thiab nthuav qhia T cell co-inhibitory nto molecules [130,131]. Yog li ntawd, kev sim kuj tseem raug tsim los txhim kho kev hloov pauv ntawm TILs uas tsom rau neoantigens hauv ntau yam malignancies [132].
Lwm qhov laj thawj rau qhov tsis ua haujlwm ntawm CAR-T cell kho hauv cov qog nqaij hlav yog xav tias suav nrog cov khoom desmoplastic (piv txwv li, cov ntaub so ntswg los yog cov ntaub so ntswg), uas tiv thaiv CAR-T hlwb los ntawm cov qog. Nws tau raug tshaj tawm tias me me hypothermia abolishes desmoplastic kev ncaj ncees hauv cov qog. Kev suav nrog me me hyperthermia thiab CAR-T cell kho tau ua rau muaj T-cell infiltration mus rau tib neeg melanoma hlav [133]. Zoo ib yam li cov tshuaj hypothermia me me, cytokines, thiab cov tshuaj chemotherapeutic kuj tau siv los txhim kho CAR-T cell infiltration ntawm ntau cov qog.
Piv txwv li, kev kho mob sib xyaw ua ke ntawm IL-12 nrog cov kws khomob kws khomob doxorubicin txhim kho kev nkag mus ntawm CD8 ntxiv rau T hlwb rau hauv cov qog, ua rau muaj kev tiv thaiv kabmob kheesxaws [134]. Lwm txoj hauv kev los txhim kho kev ua tau zoo ntawm CAR-T cell therapy hauv kev mob qog noj ntshav tuaj yeem yog kev siv CAR-T hlwb nrog rau kev thaiv ntawm T cell co-inhibitory molecules. Ntau qhov kev sim tshuaj rau daim ntawv thov ntawm CAR-T hlwb ib leeg lossis ua ke nrog CPI tau txuas ntxiv mus rau cov qog nqaij hlav. Table 4 muab piv txwv ntawm kev sim tshuaj ntawm CAR-T hlwb tiv thaiv cov qog nqaij hlav. Hauv ntau qhov kev sim tshuaj CAR-T tam sim no, cov teebmeem tshwm sim tau raug tshaj tawm vim yog kev hloov mus rau kev saws me nyuam. Yog li ntawd, txoj hauv kev tshiab rau kev siv CAR-T cell-based immunotherapy nrog txo qhov tsis zoo yuav yog qhov tseem ceeb.
Kev kho mob qog noj ntshav siv TCR-transduced T cells
CAR-T cell therapy targets surface molecules of immune cells and cannot target intracellular peptide(s) presented by major histocompatibility complexes (MHCs). Therefore, to target intracellular peptides presented by MHCs, TCR-transduced T cells have been developed [135]. These cells are generated from patient T cells and are designed to encode the TCRαβ protein, which targets tumor or virus-infected cells [136]. The large-scale production of TCR-transduced cells is achieved using semiautomated devices and modular systems [136]. TCR-transduced T cells showed prolonged survival (i.e., >18 lub hlis) thiab ua kom muaj zog txawm tias tom qab ntsib thib ob nrog antigen(s) [137].
Several tumor antigens have been used to generate TCR-transduced T cells, including trophoblast glycoprotein (TPBG) in renal cancer [138], placenta-specific 1 (PLAC1) in breast cancer [139], nucleophosmin 1 (NPM1) in acute myeloid leukemia (AML) [140], NY-ESO-1 in synovial cell sarcoma, in patients with melanoma and common epithelial tumors [141], and MAGE-A4 in esophageal cancer [142], and effectively demonstrated antitumor responses in preclinical studies. Diffuse intrinsic pontine glioma is a lethal cancer prevalent in children. In >70 feem pua ntawm diffuse intrinsic pontine glioma mob, ib qho amino acid hloov ntawm lysine (K) mus rau methionine (M) ntawm txoj hauj lwm 27 ntawm histone 3 variant 3 (H3.3) tau tshaj tawm. Interestingly, TCR-transduced T hlwb tawm tsam hluavtaws peptides nrog H3.3K27M kev hloov pauv tau npaj los kho HLAA2 ntxiv rau H3.3K27M ntxiv rau glioma hlwb [143]. Kev sim tshuaj kho mob tab tom ua kom paub tseeb qhov kev kho mob ntawm TCR-transduced T cell-raws li kev kho mob qog noj ntshav hauv cov neeg mob uas muaj ntau yam malignancies, suav nrog metastatic synovial cell sarcoma, melanoma, thiab mob qog noj ntshav [141,142]. Ua ke, TCR-transduced T cell therapy yog cov cuab yeej kho mob muaj zog nrog lub peev xwm los txhim kho T cell-mediated antitumor teb.
Kev kho mob qog noj ntshav siv TILs
CAR thiab TCR-transduced T cell-raws li kev tiv thaiv kab mob qog noj ntshav muaj txiaj ntsig zoo rau lub hom phiaj ntawm qhov chaw thiab intracellular antigens; Txawm li cas los xij, ib qho kev hloov pauv ntawm TILs tau npaj tseg uas tuaj yeem tsom cov qog antigens [144]. Hauv TIL-raws li kev kho mob qog noj ntshav, thawj kauj ruam yuav tsum txheeb xyuas cov proteins uas hloov pauv hauv cov qog. Cov protein hloov pauv tau muab tso rau hauv autologous APCs, xws li DCs. Cov kauj ruam ntxiv muaj xws li kev sib koom ua ke ntawm autologous TILs nrog antigen-loaded APCs thiab xaiv cov antigen-specific TILs. Lawv nthuav dav ua raws li kev xaiv ntawm antigen tshwj xeeb TILs. T hlwb nthuav dav siv rau kev hloov pauv hauv cov neeg mob pub dawb [132]. Qhov kev ua tau zoo ntawm TIL-based immunotherapy tau txais txiaj ntsig hauv ntau yam qog noj ntshav, suav nrog metastatic melanoma thiab metastatic human papillomavirus (HPV)-uas cuam tshuam carcinomas, zes qe menyuam thiab qog noj ntshav [145–148].
Ntau qhov kev sim tshuaj tab tom tsim los tsim cov tshuaj tiv thaiv kab mob ntawm TIL-based cancer immunotherapy ib leeg lossis ua ke nrog lwm cov tshuaj tiv thaiv kab mob hauv cov neeg mob uas muaj cov kab mob sib txawv, suav nrog lub taub hau thiab caj dab squamous cell carcinoma (IDNCT03083873), cervical carcinoma (IDNCT489030), , anaplastic thyroid cancer, osteosarcoma, los yog lwm yam pob txha thiab cov nqaij mos sarcomas (IDNCT03449108). Ua ke, TIL-raws li kev kho mob qog noj ntshav muaj peev xwm los kho cov theem siab ntawm ntau yam kev mob qog noj ntshav tsis zoo.
Cov modulators ntawm CD8 ntxiv rau T cell muaj nuj nqi
Lub luag haujlwm ntawm cov protein kinases hauv CD8 ntxiv rau T cell infiltration ntawm cov qog
CD8 ntxiv rau T cell effector muaj nuj nqi yog tswj los ntawm ntau yam, xws li antigen receptors, co-stimulatory molecules, cytokines, thiab protein kinases [149]. Interestingly, ob peb daim ntawv qhia txog dej ntws tau raug tshaj tawm tias tau hloov pauv lossis hloov kho hauv ntau yam qog nqaij hlav [77,150,151]. Txawm li cas los xij, kev sim ua kom txwv tsis pub cov dej ntws thiab cov dej ntws qis tsis tau ua tiav vim tias muaj kev tiv thaiv tshuaj tiv thaiv thiab lawv cuam tshuam rau kev tiv thaiv kab mob. Lub hauv paus yog vim li cas rau qhov tsis ua hauj lwm ntawm MAPK inhibitors yog qhov tsis muaj kev nkag siab txog cov teebmeem ntawm MAPK inhibition ntawm CD8 ntxiv rau T cell muaj nuj nqi thiab muaj sia nyob. Ntau qhov piv txwv qhia tau hais tias kev nkag siab txog lub luag haujlwm ntawm cov protein kinases hauv T cell biology yuav pab tau cov tswv yim augmenting antitumor cov lus teb, tej zaum nrog tus neeg sawv cev ntxiv. Raws li qhov piv txwv, lymphocyte muaj nuj nqi-koom nrog antigen-1 (LFA-1) kho T cell activation ntawm ERK1/2 signaling raws li TCR kev koom tes [152].
Tsis tas li ntawd, intercellular adhesion molecule-1 (ICAM-1) ligation nrog LFA-1 nce ERK1/2 signaling los txhim kho CD8 ntxiv rau T cell activation [152]. Jun N-terminal kinase (JNK), MAPK, muaj lub luag haujlwm tsis sib xws hauv kev tswj hwm ntawm CD4 ntxiv thiab CD8 ntxiv rau T hlwb [153]. Kev tshawb fawb hauv vivo siv B16, kab mob melanoma cell, thiab EL-4, kab mob qog ntshav qog ntshav, qhia tau tias JNK1-cov nas pob txha raug mob qog nqaij hlav, tshwj xeeb yog vim CD8 ntxiv rau T cell tsis ua haujlwm [ 153] ib. Kev hloov pauv hauv BRAF proto-oncogene, serine / threonine kinase, muaj lub luag haujlwm tseem ceeb hauv oncogenesis. Ib txoj kev tshawb nrhiav pom tias cov hlwb melanoma kho lub sijhawm luv (3-7 hnub) nrog BRAF inhibitor tau txais txiaj ntsig zoo los ntawm autologous CD8 ntxiv rau T hlwb (TILs). Txawm li cas los xij, cov hlwb melanoma kho tau ntev (14-21 hnub) nrog BRAF inhibitor tau pom tsis muaj zog los ntawm autologous CD8 ntxiv rau T hlwb (TILs). Cov txiaj ntsig no qhia tias BRAF inhibition sib txawv hloov cov qog antigen qhia thiab kho cov qog ua haujlwm, tej zaum los ntawm kev txo qis CD8 ntxiv rau T hlwb [154]. Lwm txoj kev tshawb fawb siv BRAF thiab MEK inhibitors (dabrafenib thiab trametinib, feem) tau pom qhov sib txawv ntawm CD8 ntxiv rau T hlwb [77]. Dabrafenib kho nyob rau hauv tib neeg-activated T hlwb (hauv vitro), induced ERK phosphorylation (ie, ua kom), thiab tsis suppress CD8 ntxiv rau T cell muaj nuj nqi.
Txawm li cas los xij, kev kho trametinib txo qis ERK phosphorylation, T-cell proliferation, thiab cytokine qhia [77]. Txawm li cas los xij, kev sib txuas ntawm trametinib nrog cov tshuaj tiv thaiv kab mob rau PD-1 lossis CTLA-4 nce CD8 ntxiv rau T cell infiltration thiab txhawb nqa cov tshuaj tiv thaiv kab mob hauv cov qauv CT26 [77]. T cell activation kuj tau tshaj tawm los txhawb TCR-ZAP-70 protein tyrosine kinase-mediated downstream signaling, uas tswj T cell motility, adhesion, thiab cytokine ntau lawm. Rasal1, GTPase-activating protein, khi nrog TCR-ZAP{13}} khi cov protein thiab inhibits Ras-ERK txoj hauv kev, T-cell ua kom, thiab cov lus teb antitumor [155]. Rasal1 tau nthuav tawm ntawm lub hlwb ua haujlwm T, thiab nws qhov knockdown induced CD8 ntxiv rau T cell infiltration hauv B16 melanoma thiab EL-4 lymphoma hlav [155]. Thaum TCR-mediated activation, qog-infiltrating CD8 ntxiv rau T hlwb pom tias txo qis ntawm ERK thiab cov protein tyrosine kinase, ITK. Txawm li cas los xij, hauv splenic CD8 ntxiv rau T hlwb, tsis muaj kev hloov pauv hauv ERK thiab ITK kinase qhia, qhia tias ERK thiab ITK kinases yog qhov sib txawv ntawm kev tswj hwm hauv peripheral thiab qog-infiltrating CD8 ntxiv rau T hlwb [156]. Sorafenib, multikinase inhibitor thiab thawj kab kev kho mob rau hepatocellular carcinoma (HCC), tuaj yeem muab cov txiaj ntsig txwv rau cov neeg mob HCC. Kev ua tiav ntawm kev kho sorafenib tau cuam tshuam nrog kev ua haujlwm ntawm ERK hauv HCC [157].
Kev soj ntsuam ntawm tib neeg thiab nas HCC cov qauv kho nrog sorafenib pom ob hom phenotypes ntawm ERK thiab PD-1 nyob rau hauv tib lub qog. Thawj phenotype yog pERKlowPD-1 ntxiv rau , qhov chaw qog infiltration ntawm CD8 ntxiv rau T hlwb yog siab heev thiab cov CD8 ntxiv rau T hlwb muaj kev qhia ntau dua ntawm PD-1. Qhov thib ob phenotype, pERKhighPD-1-, muaj qhov qhia qis ntawm PD1. Interestingly, pERKlowPD-1 ntxiv rau phenotype pom tau tias txo qis tag nrho thiab tsis muaj kab mob muaj sia nyob piv nrog pERKhighPD-1- phenotype. Qhov tseem ceeb, pERKhighPD-1- phenotype muaj CD8 ntxiv rau T hlwb nrog kev qhia qis ntawm PD-1, qhia tias qhov xwm txheej ntawm PD-1 ntawm qog-infiltrating CD8 ntxiv rau T hlwb yog qhov txiav txim siab. rau cov lus teb antitumor [158]. MAP2K (los yog MEK) yog tus tswj hwm ntawm MAPK. Lub hom phiaj inhibition ntawm MEK induced qog suppression thiab nce lifespan thiab infiltration ntawm CD8 ntxiv rau T hlwb; Txawm li cas los xij, MEK inhibition attenuated T cell priming hauv lymph nodes [151]. Hauv CT26 tus qauv qog nqaij hlav hauv BALB / c nas, kev kho mob sib xyaw ua ke ntawm kev tiv thaiv PD-L1 nrog MEK inhibitor tau pom tias muaj kev tiv thaiv zoo thiab ruaj khov, suav nrog kev tshem tawm cov qog hauv qee cov nas [151]. Lwm tus neeg hauv tsev neeg MAP3K, Mixed Lineage Kinase-3 (MLK3), muaj lub luag haujlwm paradoxical hauv kev tswj hwm ntawm cell tuag [159] thiab inhibits T cell activation thiab cytotoxicity [160].
Siv cov kab mob qog noj ntshav murine, 4T1 xenograft qauv hauv Balb / c nas, inhibition ntawm MLK3 tau pom tias ua rau cov qog infiltration ntawm cytotoxic CD8 ntxiv rau T hlwb [160]. MLK3 inhibition kuj nce CD70 qhia ntawm CD8 ntxiv rau T hlwb, cuam tshuam nrog nce apoptosis ntawm cov hlwb [161]. Interestingly, nyob rau hauv ib tug TNBC nyob rau hauv vivo qauv, ua ke kev kho mob nrog ib tug MLK3 pharmacological inhibitor thiab CD70 antagonist txhawb CD8 ntxiv rau T cell ciaj sia taus, qog infiltration, thiab antitumor efficiency [161]. MAP4K4 kuj tseem yog tus tswj hwm ntawm MAPKs. Qhov kev qhia tawm ntawm MAP4K4 inhibited LFA-1 thaum lub sij hawm T cell ua kom, thaum ablation ntawm MAP4K4 nce LFA-1 qhia ntawm CD8 ntxiv rau T hlwb. Qhov nce LFA-1 qhia ntawm T hlwb tau cuam tshuam nrog T cell sib cuam tshuam nrog APCs, uas ua rau CD8 ntxiv rau T cell effector muaj nuj nqi [162].
Lub receptor tyrosine kinase (RTK) receptor tsev neeg, epidermal growth factor receptor (EGFR), yog overexpressed nyob rau hauv epithelial cancer hlwb. Ib txoj kev tshawb nrhiav kom nkag siab tias EGFR tyrosine kinase inhibitors (TKIs) cuam tshuam li cas MHC-I hauv NSCLC hlwb tau pom tias inhibition ntawm EGFR hauv NSCLC nce cov noob thiab cov protein ntau ntawm MHC-I. T hlwb paub cov qog antigens nthuav tawm los ntawm MHC-I molecule ntawm APCs thiab xa cov lus teb rau cov tshuaj tiv thaiv. ERK-MEK inhibitor, trametinib, muaj peev xwm nce MHC-I, thaum phosphatidylinositol 3-kinase inhibitor buparlisib tsis muaj peev xwm ua rau muaj kev qhia MHC-I hauv NSCLC. Cov txiaj ntsig no qhia tias MEKERK inhibition induces EGFR-activated MHC-I qhia [163].
Lub Janus kinase / signal transducers thiab activators ntawm transcription (JAK / STAT) signaling txoj kev tswj ntau yam ntawm cytokines thiab loj hlob yam. Txawm li cas los xij, JAK2 inhibitors hauv TNBC tsis tau qhia txog qhov ua tau zoo, tej zaum vim tias TNBC hlwb tau txais platelet-derived growth factor receptor beta (PDGFR) - kho cov tshuaj tiv thaiv. Txhawm rau kov yeej qhov tsis ua haujlwm ntawm JAK2 inhibitor ua ib tus neeg sawv cev, triple ua ke kev kho mob nrog PDGFR, JAK2, thiab MEK1/2 inhibitors nce qog-infiltrating CD8 ntxiv rau T hlwb ntau [164]. Txoj kev JAK/STAT yog attenuated los ntawm cytokine-inducible SH2-muaj protein ntau (CISH) [165]. Downregulation hauv JAK/STAT signaling induced TCR-mediated activation of qog-infiltrating CD8 plus T cells [165,166]. Interestingly, induction ntawm CISH koom nrog hauv granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated DC txoj kev loj hlob, thiab DC-mediated cytotoxic T cell activation [165]. Yog li, nws yog qhov tseeb tias cov protein kinases muaj lub luag haujlwm tseem ceeb hauv CD8 ntxiv rau T cell qog infiltration, ciaj sia taus, thiab cov lus teb antitumor. Yog li, kev nkag siab zoo ntawm cov protein kinases tuaj yeem ua rau muaj kev tswj hwm ntawm ntau hom mob qog noj ntshav.
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