Nat Med | Nzira yekuongorora bundu rakabatanidzwa nenzira dzakasiyana-siyana

Nat Med | Nzira yekuongorora kenza ye colorectal ine ma "multi-omics" inoratidza kushanda kwe "microbiome" ne "immune system" yemuviri.
Kunyangwe zviratidzo zvekenza yemudumbu zvakadzidzwa zvakanyanya mumakore achangopfuura, nhungamiro dzekiriniki dziripo dzinongovimba chete nekuongorora uye kuona DNA mismatch repair (MMR) defects kana microsatellite instability (MSI) (kuwedzera pakuongororwa kwezvirwere) kuti vaone mazano ekurapa. Vaongorori vakaona kusabatana pakati pemajini expression-based immune response, microbial profiles, uye tumor stroma muCancer Genome Atlas (TCGA) colorectal cancer cohort uye kupona kwevarwere.

Sezvo tsvakiridzo ichienderera mberi, hunhu hwehuwandu hwekenza yemudumbu, kusanganisira kenza yemasero, immune, stromal, kana microbial, hwakataurwa kuti hune hukama hwakakosha nemigumisiro yekiriniki, asi kuchine kunzwisisa kushoma kwekuti kusangana kwavo kunokanganisa sei mhedzisiro yemurwere.
Kuti vaongorore hukama huripo pakati pekuomarara kwemuviri nemhedzisiro, timu yevaongorori vanobva kuSidra Institute of Medical Research muQatar munguva pfupi yapfuura vakagadzira uye vakasimbisa chibodzwa chakasanganiswa (mICroScore) chinoona boka revarwere vane mwero wakanaka wekurarama nekubatanidza hunhu hwe microbiome uye immune rejection constants (ICR). Chikwata ichi chakaita ongororo yakakwana ye genomic yemasampuli matsva akachengetwa kubva kuvarwere 348 vane primary colorectal cancer, kusanganisira RNA sequencing yemabundu uye matched healthy colorectal tissue, whole exome sequencing, deep T-cell receptor uye 16S bacterial rRNA gene sequencing, zvichiwedzerwa ne whole tumor genome sequencing kuti iwedzere kuratidza microbiome. Chidzidzo ichi chakaburitswa muNature Medicine se "An integrated tumor, immune and microbiome atlas of colon cancer".

Chinyorwa chakaburitswa muNature Medicine

Ongororo yeAC-ICAM

Vaongorori vakashandisa puratifomu ye orthogonal genomic kuongorora masampuli matsva egomarara rakaomeswa nechando uye vakafananidza tissue yekoloni ine hutano iri pedyo (bundu-normal pairs) kubva kuvarwere vane histologic diagnosis yegomarara rekoloni pasina systemic therapy. Zvichibva pa whole-exome sequencing (WES), RNA-seq data quality control, uye inclusion criteria screening, genomic data kubva kuvarwere 348 yakachengetwa uye yakashandiswa pakuongorora kwe downstream ne avhareji yekutevera kwemakore 4.6. Chikwata chevaongorori chakatumidza chinhu ichi kuti Sidra-LUMC AC-ICAM: Mepu negwara rekubatana kwe immune-cancer-microbiome (Mufananidzo 1).

Kupatsanura mamorekuru uchishandisa ICR

Vachitora modular set ye modular immune genetic markers ye continuous cancer immunosurveillance, inonzi immune constant of rejection (ICR), chikwata chekutsvagisa chakagadzirisa ICR nekuiisa muchikamu chemajini makumi maviri chinofukidza mhando dzakasiyana dzekenza, kusanganisira melanoma, kenza yedundira, uye kenza yemazamu. ICR yakabatanawo ne immunotherapy response mumhando dzakasiyana dzekenza, kusanganisira kenza yemazamu.

Kutanga, vaongorori vakasimbisa siginecha yeICR yeAC-ICAM cohort, vachishandisa nzira yeICR gene-based co-classification kuti vagovere boka iri muzvikamu zvitatu zvema clusters/immune subtypes: high ICR (hot tumors), medium ICR uye low ICR (cold tumors) (Mufananidzo 1b). Vaongorori vakaratidza kuti immune propensity inobatanidzwa ne consensus molecular subtypes (CMS), transcriptome-based classification ye colon cancer. Zvikamu zveCMS zvaisanganisira CMS1/immune, CMS2/canonical, CMS3/metabolic uye CMS4/mesenchymal. Ongororo yakaratidza kuti mamakisi eICR akanga asina hukama nedzimwe nzira dzecancer cell mumhando dzese dzeCMS, uye hukama hwakanaka ne immunosuppressive uye stromal-related pathways hwakaonekwa chete muCMS4 tumors.

MuCMS dzese, kuwanda kwemasero ekuuraya echisikigo (NK) nemasero eT kwaive kwakanyanya muICR high immune subtypes, nekusiyana kukuru mune mamwe ma leukocyte subsets (Mufananidzo 1c). Ma ICR immune subsets aive neOS nePFS dzakasiyana, nekuwedzera kuri kuita ICR kubva pasi kusvika pakakwirira (Mufananidzo 1d), zvichiratidza basa rekufanotaura reICR mukenza ye colorectal.

Mufananidzo 1. Dhizaini yekudzidza yeAC-ICAM, siginecha yemajini ane chekuita neimmune system, mhando dze immune uye molecular uye kupona.
ICR inobata masero eT akapfuma mugomarara uye akawedzerwa nemasero emuviri
Masero madiki eT anopinda munyama yegomarara chete ndiwo akataurwa kuti anonyatsoita maantigen egomarara (ari pasi pe10%). Nokudaro, masero mazhinji eT ari mukati megomarara anonzi masero eT ari pedyo (masero eT ari pedyo). Kubatana kwakasimba nehuwandu hwemasero eT ane maTCR anobereka kwakaonekwa mumasero estromal neleukocyte (akaonekwa neRNA-seq), ayo anogona kushandiswa kufungidzira mapoka eT cell (Mufananidzo 2a). Mumaboka eICR (kusanganisira CMS classification), huwandu hwepamusoro hwemaTCR eimmune SEQ hwakaonekwa mumapoka eICR-high neCMS subtype CMS1/immune (Mufananidzo 2c), nehuwandu hwakanyanya hwematumbu eICR-high. Uchishandisa transcriptome yese (majini 18,270), majini matanhatu eICR (IFNG, STAT1, IRF1, CCL5, GZMA, uye CXCL10) aive pakati pemajini gumi epamusoro akabatana neTCR immune SEQ clonality (Mufananidzo 2d). Kuumbwa kwemasero eImmunoSEQ TCR kwakabatana zvakanyanya nemajini mazhinji eICR kupfuura kuwirirana kwakaonekwa uchishandisa zviratidzo zveCD8+ zvinopindura bundu (Mufananidzo 2f na 2g). Mukupedzisa, ongororo iri pamusoro apa inoratidza kuti siginecha yeICR inoratidza kuvapo kwemasero eT ane bundu, akawedzerwa nebundu uye inogona kutsanangura zvazvinoreva pakufanotaura.

Mufananidzo 2. Zviyero zveTCR uye hukama nemajini ane chekuita neimmune, immune uye molecular subtypes.
Kuumbwa kwe microbiome mumatishu ane hutano uye ekenza yekoloni
Vaongorori vakaongorora 16S rRNA sequencing vachishandisa DNA yakatorwa kubva mubundu rakafanana uye dumbu rakanaka kubva kuvarwere 246 (Mufananidzo 3a). Kuti vasimbise, vaongorori vakaongororawo data re16S rRNA gene sequencing kubva kune mamwe masampuli 42 ebundu asina kufanana neDNA yakajairika iripo kuti aongororwe. Kutanga, vaongorori vakaenzanisa huwandu hwezvirimwa pakati pebundu rakafanana nedumbu rakanaka. Clostridium perfringens yakawedzera zvakanyanya mumabundu zvichienzaniswa nemasampuli ane hutano (Mufananidzo 3a-3d). Pakanga pasina musiyano wakakosha mukusiyana kwealpha (kusiyana uye kuwanda kwemarudzi mumuenzaniso mumwe chete) pakati pebundu nebvudzi rine hutano, uye kudzikira kudiki kwekusiyana kwehutachiona kwakaonekwa mumabundu ane ICR-high zvichienzaniswa nemabundu ane ICR-low.
Kuti vaone hukama hwakakosha pakati pemaprofile ehutachiona uye mhedzisiro yekiriniki, vaongorori vakavavarira kushandisa data re16S rRNA gene sequencing kuti vaone maficha e microbiome anofanotaura kupona. PaAC-ICAM246, vaongorori vakamhanyisa modhi yeOS Cox regression yakasarudza maficha makumi mana nerimwe ane ma coefficients asiri zero (ane chekuita nengozi yekufa yakasiyana), anonzi MBR classifiers (Mufananidzo 3f).
Muboka iri rekudzidziswa (ICAM246), chibodzwa cheMBR chakaderera (MBR<0, chibodzwa cheMBR chakaderera) chakabatana nenjodzi yakaderera yekufa (85%). Vaongorori vakasimbisa hukama huripo pakati peMBR yakaderera (njodzi) uye OS yakareba mumapoka maviri akazvimiririra akabvumidzwa (ICAM42 neTCGA-COAD). (Mufananidzo 3) Chidzidzo ichi chakaratidza hukama hwakasimba pakati pemakorokoto e endogastric cocci neMBR, ayo akafanana mubundu nematishu emukati ane hutano.

Mufananidzo 3. Microbiome iri mubundu uye munyama dzine hutano uye hukama neICR uye kurarama kwemurwere.
Mhedziso
Nzira yekuongorora masero akawanda yakashandiswa muchidzidzo ichi inoita kuti pave neruzivo rwakakwana rwekuti masero emuviri anobatsira sei pakurwisa kenza yemudumbu uye inoratidza kushanda pamwe chete kwemasero emuviri nemuviri. Kuongororwa kwakadzama kwemasero emuviri nemasero ane hutano kwakaratidza kuti mhedzisiro yeICR inogona kunge iri nekuda kwekugona kwayo kubata maT cell clones ane bundu uye pamwe antigen chaiyo yekenza.

Nekuongorora kuumbwa kwe microbiome yegomarara vachishandisa 16S rRNA gene sequencing mu AC-ICAM samples, timu iyi yakawana signature ye microbiome (MBR risk score) ine kukosha kwakasimba kwekufanotaura. Kunyangwe signature iyi yakabva mu samples dzegomarara, paive nehukama hwakasimba pakati pe colorectum ine hutano uye tumor MBR risk score, zvichiratidza kuti signature iyi inogona kubata kuumbwa kwe microbiome yegomarara revarwere. Nekubatanidza ma ICR ne MBR scores, zvaikwanisika kuona nekusimbisa multi-omic student biomarker inofanotaura kupona kwevarwere vane kenza yekoloni. Dataset yechidzidzo ichi inopa ruzivo rwekunzwisisa zviri nani biology yegomarara rekoloni uye kubatsira kuwana nzira dzekurapa dzakasarudzika.

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