Nat Med | Iyo yakawanda-omics nzira yekugadzira iyo yakasanganiswa bundu

Nat Med | Iyo yakawanda-omics nzira yekugadzira iyo yakasanganiswa bundu, immune uye microbial mamiriro e colorectal cancer inoratidza kudyidzana kweiyo microbiome ne immune system.
Kunyangwe ma biomarkers ekutanga cancer cancer akadzidzwa zvakanyanya mumakore achangopfuura, yazvino nhungamiro yekiriniki inotsamira chete pa tumor-lymph node-metastasis staging uye kuonekwa kweDNA mismatch kugadzirisa (MMR) hurema kana microsatellite kusagadzikana (MSI) (pamwe neyakajairwa pathology kuongororwa. ) kuona mazano ekurapa. Vatsvagiri vakacherekedza kushomeka kwekubatana pakati peiyo gene expression-based immune immune, microbial profiles, uye tumor stroma muCancer Genome Atlas (TCGA) colorectal cancer cohort uye kupona kwemurwere.

Sezvo tsvagiridzo yave kufambira mberi, hunhu hwehupamhi hwekutanga colorectal cancer, kusanganisira kenza cellular, immune, stromal, kana microbial chimiro chegomarara, zvakanzi zvine hukama zvakanyanya nemhedzisiro yekiriniki, asi kuchine kunzwisiswa kushoma kwekuti kusangana kwavo kunokanganisa sei mhedzisiro yemurwere. .
Kuparadzanisa hukama pakati pe phenotypic kuoma uye mhedzisiro, boka revatsvaguri kubva kuSidra Institute of Medical Research muQatar ichangobva kugadzira uye yakasimbisa chikamu chakabatanidzwa (mICRoScore) chinozivisa boka revarwere vane mararamiro akanaka ekupona nekubatanidza hunhu hwemicrobiome uye kurambwa kwemuviri. zvinoramba zviripo (ICR). Chikwata ichi chakaita ongororo yakadzama yemasampu akaomeswa nechando kubva kuvarwere mazana matatu nemakumi mana nevasere vane chirwere chegomarara rekutanga, kusanganisira RNA kutevedzana kwemamota uye yakaenzana ine hutano colorectal tishu, yakazara exome sequencing, yakadzika T-cell receptor uye 16S bhakitiriya rRNA gene sequencing, yakawedzerwa nebundu rose. genome sequencing kuti uwedzere kuratidza iyo microbiome. Chidzidzo ichi chakaburitswa muNature Medicine se "Bundu rakasanganiswa, immune uye microbiome atlas yecolon cancer".

Chinyorwa chakaburitswa muNature Medicine

AC-ICAM Overview

Vatsvagiri vakashandisa orthogonal genomic chikuva kuongorora nyowani bundu rakaomeswa nechando uye kuenzanisa padyo neine hutano colon tishu (tumor-yakajairika pairs) kubva kuvarwere vane histologic kuongororwa kwecolon cancer pasina systemic therapy. Kubva pane yakazara-exome sequencing (WES), RNA-seq data quality control, uye inclusion criteria yekuongorora, genomic data kubva kuvarwere ve348 yakachengetwa uye yakashandiswa pakuongorora kwakadzika nekutevera kwepakati pemakore 4.6. Chikwata chekutsvagisa chakatumidza sosi iyi Sidra-LUMC AC-ICAM: Mepu uye gwara kune immune-kenza-microbiome kusangana (Mufananidzo 1).

Molecular classification uchishandisa ICR

Kubata modular seti yeaimmune genetic mamaki ekuenderera mberi kwegomarara immunosurveillance, inonzi immune constant rejection (ICR), timu yekutsvagisa yakagadziridza ICR nekuiisa mu 20-gene panel inovhara mhando dzakasiyana dzegomarara, kusanganisira melanoma, cancer yedundira, uye. kenza yemazamu. ICR yakave yakabatanidzwawo ne immunotherapy mhinduro mumhando dzakasiyana dzekenza, kusanganisira kenza yemazamu.

Chekutanga, vaongorori vakasimbisa iyo ICR siginecha ye AC-ICAM cohort, vachishandisa ICR gene-based co-classification nzira yekuisa iyo cohort kuita matatu masumbu / immune subtypes: yakakwira ICR (anopisa tumors), yepakati ICR uye yakaderera ICR (inotonhora. mapundu) (Mufananidzo 1b). Vatsvaguri vakaratidzira immune propensity yakabatana nekubvumirana molecular subtypes (CMS), transcriptome-based classification yecolon cancer. zvikamu zveCMS zvaisanganisira CMS1/immune, CMS2/canonical, CMS3/metabolic uye CMS4/mesenchymal. Ongororo yakaratidza kuti zvibodzwa zveICR zvakabatana zvisina kunaka nedzimwe nzira dzegomarara mune ese CMS subtypes, uye kuwirirana kwakanaka ne immunosuppressive uye stromal-ane hukama nzira dzakaonekwa chete muCMS4 tumors.

MuCMS yese, kuwanda kwemuurayi wechisikigo (NK) cell uye T cell subsets yaive yakakwirira muICR yakakwira immune subtypes, nekusiyana kukuru mune mamwe leukocyte subsets (Figure 1c) .ICR immune subtypes yaive neOS yakasiyana uye PFS, nekuwedzera kunowedzera. muICR kubva pasi kusvika kumusoro (Mufananidzo 1d), kusimbisa basa rekufungidzira reICR mune colorectal cancer.

Mufananidzo 1. AC-ICAM yekudzidza dhizaini, immune-yakabatana gene siginecha, immune uye molecular subtypes uye kupona.
ICR inobata tumor-yakapfuma, clonally amplified T masero
Vashoma chete masero eT anopinda nebundu tishu anonzi akajeka kune tumor antigens (pasi pegumi muzana). Naizvozvo, ruzhinji rwe intra-tumor T masero anonzi anomira T masero (amire T masero). Kubatana kwakasimba nenhamba yemasero eT akajairika ane TCRs anobereka akaonekwa mu stromal cell uye leukocyte subpopulations (yakaonekwa neRNA-seq), iyo inogona kushandiswa kufungidzira T cell subpopulations (Mufananidzo 2a). MuICR zvikwata (zvese uye CMS kupatsanurwa), iyo yepamusoro-soro clonality yeimmune SEQ TCRs yakaonekwa muICR-yakakwirira uye CMS subtype CMS1/mapoka ekudzivirira zvirwere (Figure 2c), ine chikamu chepamusoro-soro cheICR-yakakwirira mapundu. Kushandisa iyo yose transcriptome (18,270 genes), matanhatu ICR genes (IFNG, STAT1, IRF1, CCL5, GZMA, uye CXCL10) yaiva pakati pemajeni gumi epamusoro akabatanidzwa neTCR immune SEQ clonality (Mufananidzo 2d). ImmunoSEQ TCR clonality yakabatana zvakanyanya neakawanda ICR majini pane kuwirirana kunoonekwa uchishandisa tumor-inopindura CD8+ mamaki (Mufananidzo 2f uye 2g). Mukupedzisa, ongororo iri pamusoro inoratidza kuti iyo ICR siginecha inobata kuvepo kwebundu-yakafumiswa, clonally amplified T masero uye inogona kutsanangura zvarinoreva.

Mufananidzo 2. TCR metrics uye kuwirirana nemajini ane hukama, immune uye molecular subtypes.
Microbiome kuumbwa mune hutano uye colon cancer tishu
Vatsvakurudzi vakaita 16S rRNA sequencing vachishandisa DNA yakatorwa kubva kune inofananidzwa nebundu uye ine hutano colon tissue kubva kuvarwere ve246 (Mufananidzo 3a). Kuti zvisimbiswe, vaongorori vakaongororazve 16S rRNA gene rekuteedzera data kubva kune mamwe makumi mana nemaviri tumor samples akange asina kuenderana neyakajairika DNA inowanikwa kuti iongororwe. Chekutanga, vaongorori vakafananidza kuwanda kwemaruva pakati pemamota anofanana uye ane hutano colon tishu. Clostridium perfringens yakawedzera zvakanyanya mumamota kana ichienzaniswa nemasampuri ane hutano (Mufananidzo 3a-3d). Pakanga pasina mutsauko unokosha mukusiyana kwealpha (kusiyana uye kuwanda kwezvipenyu mumuenzaniso mumwe chete) pakati pebundu uye masampuri ane hutano, uye kudzikisira zvine mwero mukusiyana kwehutachiona kwakaonekwa muICR-yakakwirira mapundu maererano neICR-yakaderera mapundu.
Kuti vaone hukama hunoenderana nekiriniki pakati pemicrobial profiles uye mhedzisiro yekiriniki, vatsvakurudzi vane chinangwa chekushandisa 16S rRNA gene sequencing data kuona microbiome maficha anofanotaura kupona. PaAC-ICAM246, vaongorori vakamhanyisa OS Cox regression modhi iyo yakasarudza 41 maficha ane asiri-zero coefficients (akabatana nekusiyana kwenjodzi yekufa), inonzi MBR classifiers (Figure 3f).
Muchikwata ichi chekudzidzisa (ICAM246), chikamu cheMBR chakaderera (MBR <0, pasi MBR) chakabatanidzwa nehuwandu hwehuwandu hwekufa (85%). Vatsvagiri vakasimbisa kushamwaridzana pakati peyakaderera MBR (njodzi) uye yakarebesa OS mune maviri akazvimirira akasimbiswa cohorts (ICAM42 uye TCGA-COAD). (Mufananidzo 3) Chidzidzo chacho chakaratidza kuwirirana kwakasimba pakati pe endogastric cocci uye MBR scores, iyo yakanga yakafanana mumarara uye hutano hwehutano.

Mufananidzo 3. Microbiome mune bundu uye hutano tishu uye hukama neICR uye kurarama kwemurwere.
Mhedziso
Iyo yakawanda-omics nzira inoshandiswa muchidzidzo ichi inogonesa kunyatsoonekwa uye kuongororwa kwema molecular siginecha ye immune system mu colorectal cancer uye inoratidza kudyidzana pakati pemicrobiome uye immune system. Yakadzika TCR kutevedzana kwebundu uye matishu ane hutano kwakaratidza kuti fungidziro yeICR inogona kunge iri nekuda kwekugona kwayo kubata bundu-rakapfumisa uye pamwe tumor antigen-chaiwo T cell clones.

Nekuongorora tumor microbiome kuumbwa uchishandisa 16S rRNA gene sequencing muAC-ICAM samples, timu yakaona microbiome siginecha (MBR njodzi mamaki) ine yakasimba prognostic kukosha. Kunyangwe iyi siginecha yakatorwa kubva kumasampure emabundu, pakanga paine kuwirirana kwakasimba pakati pehutano colorectum uye bundu MBR njodzi mamakisi, zvichiratidza kuti siginecha iyi inogona kubata gut microbiome kuumbwa kwevarwere. Nekubatanidza iyo ICR neMBR zvibodzwa, zvaigoneka kuona uye kusimbisa iyo yakawanda-omic mudzidzi biomarker inofanotaura kupona muvarwere vane colon cancer. Iyo yekudzidza yakawanda-omic dataset inopa sosi yekunzwisisa zviri nani colon cancer biology uye kubatsira kuwana yakasarudzika nzira dzekurapa.

Reference
Roelands, J., Kuppen, PJK, Ahmed, EI et al. Bundu rakabatanidzwa, immune uye microbiome atlas yecolon cancer. Nat Med 29, 1273–1286 (2023).