Immunophenotyping Ntawm Cov Tumor Microenvironment

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Cov qog nqaij hlav feem ntau yog nyob ntawm microenvironment uas nws nyob, thiab cov qog tiv thaiv kab mob microenvironment (TIME) yog ib qho nyuaj heev, uas muaj ntau lub cev tiv thaiv kab mob, stromal hlwb thiab cytokines tuaj yeem cuam tshuam nrog cov qog. Kev tswj hwm ntawm cov kab ke tiv thaiv kab mob no muaj kev sib cuam tshuam nrog cov qog thiab muaj qhov cuam tshuam tseem ceeb rau kev loj hlob ntawm cov qog thiab cov tshuaj tiv thaiv kab mob.

Cov txiaj ntsig ntawmcistanche: tiv thaiv qog thiab txhim khoqog immune microenvironment

Zuag qhia tag nrho immunophenotype ntawm qog microenvironment

Tag nrho cov xwm txheej ntawm qog-infiltrating lymphocytes (TILs) hauv cov qog microenvironment (TME) muaj feem cuam tshuam nrog kev ua tau zoo ntawm kev tiv thaiv kab mob. Cov duab kab mob qog noj ntshav tuaj yeem tau txais los ntawm kev kawm tob-los ntawm "lub computer staining" thiab siv rau Kev Qhia Txog TILs. Raws li cov xwm txheej ntawm lub cev tiv thaiv kab mob hauv SIJ HAWM, cov qauv qog tiv thaiv kab mob tuaj yeem muab faib ua peb hom: hom kab mob tiv thaiv kab mob, hom kab mob tiv thaiv kab mob thiab hom kab mob tiv thaiv kab mob. Hom kab mob tiv thaiv kab mob yog tus cwj pwm los ntawm qhov muaj CD8 ntxiv thiab CD4 ntxiv rau T hlwb hauv cov qog parenchyma, nrog rau kev qhia ntawm lub cev tiv thaiv kab mob, qhia tias cov qog no muaj peev xwm tiv thaiv kab mob tiv thaiv kab mob rau ICIs. Hom kev tiv thaiv kab mob tsis suav nrog yog tus cwj pwm los ntawm qhov muaj cov kab mob sib txawv ntawm cov kab mob hauv cov kab mob hnyav lossis stroma ntawm cov qog, tab sis tsis nkag mus rau cov qog parenchyma. Cov kev tshawb fawb tau txheeb xyuas cov qauv ua ntej kev kho mob tiv thaiv kev tuag ntawm tes 1 (PD-1) / thiab nws ligand (programmed cell death-ligand 1, PD-L1), thiab cov txiaj ntsig tau pom tias cov neeg teb tau cuam tshuam CD8 ntxiv rau T cell abundance yog kuj siab ntawm cov npoo ntawm kev sib deev, thiab serial sampling thaum lub sij hawm kev kho mob pom tau tias muaj kev nce hauv CD8 ntxiv rau T cell infiltration ntawm cov qog parenchyma. Hom suab puam tiv thaiv kab mob yog tus cwj pwm los ntawm qhov tsis muaj T-hlwb ntau hauv cov qog parenchyma lossis stroma, uas ua rau tsis zoo rau ICIs. Tsis ntev los no, cov qhab nia tiv thaiv kab mob tau raug npaj los ua qhov qhia tau zoo rau tus yam ntxwv TME tiv thaiv kab mob, kev faib cov qog, thiab kwv yees cov lus teb thiab kev kuaj mob, suav nrog kev qhia ntawm ob tus neeg lymphocytes (CD8 ntxiv thiab nco [CD45RO ntxiv] T hlwb) hauv center thiab qog invasive margins. ceev. MLECNIK thiab al soj ntsuam cov qhab nia tiv thaiv kab mob hauv 599 tus neeg mob ntawm theem I-IV kab mob qog noj ntshav thiab tau lees paub tias nws muaj feem cuam tshuam nrog kev muaj sia nyob tsis muaj sia nyob (PFS) thiab kev ciaj sia tag nrho (OS) ntawm cov neeg mob qog, thiab ntau qhov kev tshuaj ntsuam xyuas kuj tau pom tias superiority ntawm kev tiv thaiv cov qhab nia hauv kev kwv yees kab mob rov qab thiab ciaj sia. Tus nqi ntawm cov qhab nia tiv thaiv kab mob hauv kev kwv yees qhov ua tau zoo ntawm ICIs txoj kev kho tau raug lees paub hauv kev sim tshuaj kho mob melanoma thiab mob qog noj ntshav tsis me me (NSCLC).

Txhim kho kev tiv thaiv kab mob thiab tiv thaiv qog: cistamche ntxiv hmoov

Ib txoj kev tshawb fawb tau siv cov ntaub ntawv sau tseg los txheeb xyuas cov TME thiab tau lees paub tias microenvironmental subtypes tuaj yeem siv los ua tus kwv yees ntawm kev siv tshuaj tiv thaiv kab mob. Cov kws tshawb fawb thawj zaug tshawb nrhiav cov ntaub ntawv luam tawm rau kev ua haujlwm ntawm cov noob caj noob ces kos npe (Fges) ntawm TME cov khoom (xws li qog cov ntsiab lus tseem ceeb, lub cev tiv thaiv kab mob, cov hlwb stromal, thiab lwm cov cell cell); tom qab ntawd tsim ib qho kev nthuav dav Delineate ib qho qauv ntawm TME; Tom qab ntawd siv ntau cov ntaub ntawv xws li Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), lossis Genotype-Tissue Expression (GTEx) Qhov tseeb ntawm Fges kev faib tawm tau siv tau nrog cov ntaub ntawv hauv thiab pom tias muaj ntau hom cell. tshwj xeeb, xws li kev qhia ntawm cov noob yam ntxwv ntawm cov qog proliferation (nrog rau lub voj voog ntawm tes thiab cov qog kev loj hlob ntawm cov noob caj noob ces) piv nrog cov ntaub so ntswg thiab moles. Malignant melanoma muaj kev sib raug zoo; Thaum kawg, 29 Fges tau siv los txheeb xyuas melanoma TME thiab muab faib ua 4 microenvironmental subtypes hauv qab no: (1) tiv thaiv kab mob thiab fibrotic (Immune-enriched, fibrotic, IE / F); (2) Kev tiv thaiv kab mob, uas tsis yog-fibrotic (immune-enriched, fibrotic, IE); (3) fibrotic (fibrotic, F); (4) kev tiv thaiv kab mob tsis txaus (immune-depleted, D). Cov lus hais saum toj no sib txawv TME subtypes yog qhov sib txawv loj, muaj kev sib raug zoo nrog kev siv tshuaj tiv thaiv kab mob, thiab tuaj yeem siv los ua qhov kev kwv yees biomarkers. Piv txwv li, hauv cov tshuaj tiv thaiv cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy, cov neeg mob cutaneous melanoma hom IE muaj 82 feem pua ​​​​cov lus teb rau kev kho mob, piv nrog 10 rau hom F feem pua, thiab IE OS yog qhov ntev tshaj plaws. Tsis tas li ntawd, los ntawm kev tshuaj xyuas ua ntej thiab tom qab immunotherapy, qhov kev hloov pauv hloov pauv ntawm TME rau kev tiv thaiv kab mob kuj tuaj yeem pom. Piv txwv li, ntawm cov neeg mob melanoma tau txais kev kho mob los tiv thaiv PD-1, cov neeg teb tau pib IE / F lossis IE, uas tseem tsis tau hloov pauv thaum kho lossis txhim kho rau hauv ib puag ncig tiv thaiv kab mob; thaum tsis teb cov lus teb feem ntau yog F TMEs hom, uas zoo nkaus li tswj lossis txav mus rau kev tiv thaiv TME thaum kho. Qhov kev faib tawm TME no kuj tseem tuaj yeem piav qhia txog qhov ua tau zoo ntawm kev tiv thaiv kab mob hauv cov neeg mob uas muaj cov qog nqaij hlav qis (TMB), thiab hauv kev nthuav dav uas tsis muaj cov ntaub ntawv TMB, TME kev faib tawm siv kev kho mob ua ntej thiab kev kho mob biopsies tseem muaj peev xwm kwv yees tau zoo. Yog li ntawd, ob txoj kev faib tawm, TME ntaus ntawv thiab TMB tsom xam, tuaj yeem sib ntxiv ua ke raws li kev tiv thaiv kab mob biomarkers.

Dragon tshuaj ntsuab: cistamche

Tshwj xeeb microenvironmental immunophenotypes

Ntxiv nrog rau tag nrho cov tiv thaiv kab mob phenotype ntawm microenvironment, kev qhia ntawm qee cov molecules ntawm lub cev tiv thaiv kab mob lossis cov hlwb stromal hauv TME tuaj yeem ua tus yam ntxwv tshwj xeeb ntawm lub cev tiv thaiv kab mob hauv microenvironment, yog li cuam tshuam rau kev ua tau zoo ntawm kev tiv thaiv kab mob, thiab tau maj mam tshawb xyuas raws li kev kwv yees. marker rau immunotherapy. . Cov kev tshawb fawb tsis ntev los no tau pom tias CD28 tuaj yeem siv los ua tus cim kev kwv yees rau kev siv tshuaj tiv thaiv kab mob, thiab raws li qhov no, cov tshuaj tiv thaiv kab mob tshiab tuaj yeem tsim kho. Nyob rau hauv sib piv rau CTLA-4, CD28 yog ib tug co-stimulatory receptor uas cuam tshuam nrog CD80/86 los hloov lub cev tsis muaj zog, ua kom muaj ntau yam txheej txheem uas txhawb kev tiv thaiv kab mob. T lymphocyte tyrosine kinase (LCK), phosphatidylinositol 3-kinase (PI3K) txoj hauv kev thiab protein kinase C (PKC) thiab lwm yam kev taw qhia tuaj yeem qhib CD28, thiab tom qab ntawd ua kom muaj ntau yam kev hloov pauv hauv qab, xws li activator protein{{ 9}} (AP-1) thiab nuclear factor-κB (nuclear transcription factor-κB, NF-κB). Cov kev hloov pauv no yog qhov tseem ceeb rau IL-2 ntau lawm thiab T cell ua kom muaj sia nyob. KAMPHORST et al. pom tias CD28 signaling plays lub luag haujlwm tseem ceeb hauv kev ua kom thiab rov ua haujlwm ntawm CD8 ntxiv rau T cell proliferation thiab tiv thaiv qog. Anti-PD-1 kev kho mob muaj kev xaiv nthuav dav ntawm CD28 ntxiv rau cov hlwb. Yog li, nws raug pom zoo kom siv CD28 ua tus kwv yees ntawm CD8 ntxiv rau T hlwb hauv cov neeg mob qog. Muaj peev xwm biomarkers ntawm cov lus teb. Tsis tas li ntawd, PD-1 inhibits signaling los ntawm T cell receptor (TCR) tom qab tau qhib los ntawm nws ligand PD-L1. Los ntawm kev kuaj pom PD-1 teeb liab hauv biochemical reconstitution system, HUI li al. pom tias cov co-stimulatory receptor CD28 muaj feem ntau dua TCR raws li lub hom phiaj rau PD-1 los nrhiav Shp2 phosphatase dephosphorylation; PD-1 qhib los ntawm L1 nyiam dephosphorylates, tsis yog TCR. Yog li ntawd, nws ntseeg tau tias PD-1 feem ntau inhibits T cell muaj nuj nqi los ntawm inactivating CD28 signaling, qhia tias txoj kev co-stimulatory plays lub luag hauj lwm tseem ceeb hauv kev tswj effector T cell (Teffs) muaj nuj nqi thiab anti-PD-L1 / PD. -1 kho cov nyhuv. Nyob rau hauv lub neej yav tom ntej, kev cawm ntawm T cell depletion phenotype los ntawm zoo dua thaiv PD-1 khi rau CD28 tej zaum yuav muaj peev xwm ua tau zoo antitumor immunotherapy lub tswv yim.

cistamche tshuaj yej txhim kho kev tiv thaiv kab mob thiab tiv thaiv qog thiab mob qog noj ntshav

Ntxiv nrog rau kev ua kom cov molecules, kev qhia txog kev tiv thaiv kab mob ntawm lub cev tiv thaiv kab mob kuj yog ib qho kev xav ntawm lub cev tiv thaiv kab mob phenotype ntawm ib qho microenvironment tshwj xeeb, uas tuaj yeem cuam tshuam thiab kwv yees qhov ua tau zoo ntawm kev tiv thaiv kab mob. Ntawm lawv, PD-1 yog qhov kev tshawb fawb tshaj plaws thiab siv dav siv tshuaj ntsuam xyuas molecule. Cov kev tshawb fawb tau pom tias qhov sib npaug ntawm PD-1 kev qhia ntawm effector T hlwb thiab kev tswj T hlwb (Tregs) hauv TME tuaj yeem kwv yees qhov kev kho mob zoo ntawm PD-1 blockade therapy. Txoj kev tshawb no tau siv cov cytometry ntws los tshawb xyuas TILs thiab pom tias qhov piv ntawm PD-1 ntxiv rau CD8 ntxiv rau T hlwb / PD-1 ntxiv rau Tregs hlwb hauv TME ntawm cov neeg mob uas muaj txiaj ntsig thiab tsis muaj txiaj ntsig PD-1 Kev kho mob monoclonal antibody yog qhov sib txawv heev, thiab TME ntawm cov neeg mob nrog kev kho mob zoo sib txawv heev. Muaj kev nkag siab siab ntawm PD-1 ntxiv rau CD8 ntxiv rau T hlwb hauv TME, thiab CD8 ntxiv rau T hlwb nrog siab PD-1 kev qhia muaj cov tshuaj tiv thaiv kab mob siab peptides; ntawm qhov tsis sib xws, PD-1 tau qhia ntau heev nyob rau hauv effector Treg hlwb hauv TME ntawm cov neeg mob kho tsis zoo. Lwm cov tshuaj tiv thaiv kab mob qog noj ntshav tshiab yog T-cell immunoglobulin thiab ITIM domain (T-cell immunoglobulin thiab immunoreceptor tyrosine-based inhibitory motif domain, TIGHT), uas koom nrog hauv lymphocytes, tshwj xeeb tshaj yog nyob rau hauv effector CD8 ntxiv rau T hlwb thiab cov tshuaj tua kab mob ntuj tsim. qhia nyob rau hauv natural killer cells (NK). TIGIT tuaj yeem cuam tshuam lub cev tiv thaiv kab mob hauv ntau kauj ruam ntawm lub qog tiv thaiv kab mob. Thaum TIGIT nyob rau saum npoo ntawm NK hlwb thiab T hlwb khi rau cov kab mob poliovirus receptor (PVR, lossis CD155) ntawm cov qog hlwb, cov qog cell tua cov teebmeem ntawm NK hlwb thiab T hlwb raug inhibited. Kev tiv thaiv qog nqaij hlav tuaj yeem rov qab los thaum tiv thaiv TIGIT los ntawm kev khi rau nws cov ligands. Piv txwv li, MK-7684 yog humanized IgG1 monoclonal antibody uas khi TIGIT thiab thaiv nws cov kev cuam tshuam nrog nws cov ligands CD112 thiab CD155 (NCT02964013, NCT04305041). Tsis tas li ntawd, lub cev tiv thaiv kab mob kuj tseem tuaj yeem nthuav tawm lwm yam inhibitory receptors, xws li CTLA-4, T cell immunoglobulin thiab mucin-muaj molecule 3 (TIM{29}}), thiab lwm yam, uas ua rau cov qog tsis muaj zog. THOMSEN et al. pom tias muaj kev sib koom ua ke ntawm ntau qhov chaw tiv thaiv kab mob, xws li PD-1, TIM-3, CTLA-4, thiab lymphocyte activation gene-3 (LAG-3 ), tuaj yeem txhawb txoj kev loj hlob ntawm T cell Kev sib deev hnyav hnyav, uas ntxiv kev kho kom haum xeeb ntawm kev tiv thaiv rau ICIs. Muab ua ke, cov lus qhia ntawm cov tshuaj tiv thaiv kab mob thiab cov tshuaj tiv thaiv molecules tuaj yeem sawv cev rau microenvironment-specific immunophenotypic kos npe, uas tsis tsuas yog muaj txiaj ntsig zoo hauv kev kwv yees cov txiaj ntsig kho mob ntawm ICIs tab sis kuj pab txhawb kev txhim kho ntawm cov tswv yim tiv thaiv kab mob tsom rau cov molecules.