Nat Med | Njira yogwiritsira ntchito ma tomics ambiri pojambula chotupa chophatikizidwa

Nat Med | Njira yowonera khansa ya m'matumbo, chitetezo chamthupi, ndi tizilombo toyambitsa matenda imasonyeza momwe microbiome imagwirira ntchito ndi chitetezo chamthupi.
Ngakhale kuti zizindikiro za khansa ya m'matumbo akuluakulu zaphunziridwa kwambiri m'zaka zaposachedwapa, malangizo azachipatala omwe alipo panopa amadalira kokha pa kukhazikika kwa maselo a khansa ya m'matumbo ndi kuzindikira zolakwika za DNA mismatch repair (MMR) kapena kusakhazikika kwa microsatellite (MSI) (kuphatikiza pa mayeso okhazikika a matenda) kuti adziwe malangizo a chithandizo. Ofufuza awona kusowa kwa mgwirizano pakati pa mayankho a chitetezo chamthupi omwe amachokera ku majini, ma microbial profiles, ndi tumor stroma mu gulu la khansa ya m'matumbo la Cancer Genome Atlas (TCGA) ndi kupulumuka kwa odwala.

Pamene kafukufuku wapita patsogolo, zizindikiro za kuchuluka kwa khansa yoyambirira ya m'matumbo, kuphatikizapo khansa ya maselo, chitetezo chamthupi, stromal, kapena microbial, zanenedwa kuti zikugwirizana kwambiri ndi zotsatira zachipatala, koma pakadalibe kumvetsetsa kochepa momwe kuyanjana kwawo kumakhudzira zotsatira za odwala.
Pofuna kupeza ubale pakati pa zovuta za phenotypic ndi zotsatira zake, gulu la ofufuza ochokera ku Sidra Institute of Medical Research ku Qatar posachedwapa adapanga ndikutsimikizira chiŵerengero chophatikizidwa (mICroScore) chomwe chimazindikira gulu la odwala omwe ali ndi kuchuluka kwabwino kopulumuka mwa kuphatikiza makhalidwe a microbiome ndi zokhazikika zokana chitetezo chamthupi (ICR). Gululi lidachita kusanthula kwathunthu kwa majini a zitsanzo zatsopano zozizira kuchokera kwa odwala 348 omwe ali ndi khansa yoyamba ya colon, kuphatikiza RNA sequencing ya zotupa ndi minofu ya colonectal yathanzi, sequencing yonse ya exome, deep T-cell receptor ndi 16S bacterial rRNA gene sequencing, yowonjezera ndi sequencing yonse ya chotupa kuti iwonetse bwino microbiome. Kafukufukuyu adasindikizidwa mu Nature Medicine ngati "An integrated chotupa, immune and microbiome atlas of colon cancer".

Nkhani yofalitsidwa mu Nature Medicine

Chidule cha AC-ICAM

Ofufuza adagwiritsa ntchito njira yolumikizira majini kuti afufuze zitsanzo zatsopano za chotupa chozizira komanso kufananiza minofu ya m'matumbo yathanzi (ma pairs a chotupa-abwinobwino) ochokera kwa odwala omwe adapezeka ndi khansa ya m'matumbo popanda chithandizo chamankhwala. Kutengera ndi kusanthula kwa exome yonse (WES), kuwongolera kwa data ya RNA-seq, ndikuwunika njira zophatikizira, deta ya majini kuchokera kwa odwala 348 idasungidwa ndikugwiritsidwa ntchito pofufuza pambuyo pake ndi kutsata kwapakati kwa zaka 4.6. Gulu lofufuza lidatcha chida ichi Sidra-LUMC AC-ICAM: Mapu ndi chitsogozo cha kuyanjana kwa chitetezo chamthupi-khansa-microbiome (Chithunzi 1).

Kugawa maselo pogwiritsa ntchito ICR

Pogwira seti ya majini oteteza chitetezo chamthupi kuti azitha kuyang'aniridwa ndi khansa mosalekeza, yotchedwa immunoconstant of rejection (ICR), gulu lofufuza linakonza ICR mwa kuichepetsa kukhala gulu la majini 20 lomwe lili ndi mitundu yosiyanasiyana ya khansa, kuphatikizapo melanoma, khansa ya chikhodzodzo, ndi khansa ya m'mawere. ICR yakhala ikugwirizananso ndi yankho la immunotherapy m'mitundu yosiyanasiyana ya khansa, kuphatikizapo khansa ya m'mawere.

Choyamba, ofufuzawo adatsimikizira siginecha ya ICR ya gulu la AC-ICAM, pogwiritsa ntchito njira ya ICR yophatikiza majini kuti agawane gululo m'magulu atatu/magulu a chitetezo chamthupi: ICR yayikulu (zotupa zotentha), ICR yapakati ndi ICR yotsika (zotupa zozizira) (Chithunzi 1b). Ofufuzawo adazindikira mphamvu ya chitetezo chamthupi yogwirizana ndi magulu a maselo a consensus (CMS), gulu lozikidwa pa transcriptome la khansa ya m'matumbo. Magulu a CMS adaphatikizapo CMS1/immune, CMS2/canonical, CMS3/metabolic ndi CMS4/mesenchymal. Kusanthula kunawonetsa kuti ziwerengero za ICR zinali zogwirizana molakwika ndi njira zina za maselo a khansa m'magulu onse a CMS, ndipo kulumikizana kwabwino ndi njira zokhudzana ndi chitetezo chamthupi komanso stromal kunawonedwa mu zotupa za CMS4 zokha.

Mu CMS yonse, kuchuluka kwa maselo achilengedwe opha (NK) ndi maselo a T kunali kwakukulu kwambiri mu mitundu ya ICR yokhala ndi chitetezo chamthupi chambiri, ndipo kusiyana kwakukulu mu mitundu ina ya leukocyte (Chithunzi 1c). Mitundu ya chitetezo chamthupi ya ICR inali ndi OS ndi PFS zosiyana, ndi kuwonjezeka pang'onopang'ono kwa ICR kuchokera pansi mpaka pamwamba (Chithunzi 1d), zomwe zimatsimikizira udindo wa ICR wolosera khansa ya m'matumbo.

Chithunzi 1. Kapangidwe ka kafukufuku wa AC-ICAM, chizindikiro cha majini okhudzana ndi chitetezo chamthupi, mitundu ya chitetezo chamthupi ndi mamolekyulu komanso kupulumuka.
ICR imagwira maselo a T opangidwa ndi chotupa komanso opangidwa ndi maselo enaake
Maselo ochepa okha a T omwe amalowa mu minofu ya chotupa ndi omwe anenedwa kuti ndi enieni a ma antigen a chotupa (osakwana 10%). Chifukwa chake, maselo ambiri a T omwe ali mkati mwa chotupa amatchedwa maselo a T omwe amangoyang'ana (maselo a T omwe amangoyang'ana). Kugwirizana kwakukulu ndi chiwerengero cha maselo a T omwe ali ndi ma TCR opangidwa bwino kunawonedwa mu maselo a stromal ndi ma leukocyte subpopulations (omwe amapezeka ndi RNA-seq), omwe angagwiritsidwe ntchito kuwerengera magulu a maselo a T (Chithunzi 2a). Mu magulu a ICR (onse ndi gulu la CMS), kuchuluka kwa ma TCR a immune SEQ TCRs kunawonedwa mu magulu a ICR-high ndi CMS subtype CMS1/immune (Chithunzi 2c), ndi chiwerengero chachikulu cha zotupa za ICR-high. Pogwiritsa ntchito transcriptome yonse (majini 18,270), majini asanu ndi limodzi a ICR (IFNG, STAT1, IRF1, CCL5, GZMA, ndi CXCL10) anali m'gulu la majini khumi apamwamba omwe amagwirizana ndi TCR immune SEQ clonality (Chithunzi 2d). Kuchuluka kwa maselo a ImmunoSEQ TCR kunagwirizana kwambiri ndi majini ambiri a ICR kuposa momwe maselo a CD8+ omwe amayankha khansa amagwirira ntchito (Chithunzi 2f ndi 2g). Pomaliza, kusanthula komwe kwatchulidwa pamwambapa kukusonyeza kuti chizindikiro cha ICR chikuwonetsa kupezeka kwa maselo a T omwe ali ndi khansa komanso omwe amakula ndi maselo ena ndipo chingafotokoze zomwe zimayambitsa matenda.

Chithunzi 2. Miyeso ya TCR ndi mgwirizano ndi majini okhudzana ndi chitetezo chamthupi, magulu a chitetezo chamthupi ndi mamolekyulu.
Kapangidwe ka microbiome m'maselo a khansa ya m'matumbo komanso yathanzi
Ofufuzawo adachita kafukufuku wa 16S rRNA pogwiritsa ntchito DNA yochokera ku chotupa chofanana ndi minofu ya m'matumbo yathanzi kuchokera kwa odwala 246 (Chithunzi 3a). Kuti atsimikizire, ofufuzawo adasanthulanso deta yotsatizana ya majini a 16S rRNA kuchokera ku zitsanzo zina 42 za chotupa zomwe sizinafanane ndi DNA yachibadwa yomwe ilipo kuti iwunikidwe. Choyamba, ofufuzawo adayerekeza kuchuluka kwa zomera pakati pa zotupa zofanana ndi minofu ya m'matumbo yathanzi. Clostridium perfringens idawonjezeka kwambiri m'zotupa poyerekeza ndi zitsanzo zathanzi (Chithunzi 3a-3d). Panalibe kusiyana kwakukulu pakusiyana kwa alpha (kusiyanasiyana ndi kuchuluka kwa mitundu mu chitsanzo chimodzi) pakati pa zitsanzo za chotupa ndi zathanzi, ndipo kuchepa pang'ono kwa kusiyanasiyana kwa tizilombo tating'onoting'ono kunawonedwa mu zotupa za ICR-high poyerekeza ndi zotupa za ICR-low.
Pofuna kupeza mgwirizano wofunikira pakati pa ma virus ndi zotsatira zachipatala, ofufuzawo adafuna kugwiritsa ntchito deta ya 16S rRNA gene sequencing kuti adziwe zinthu za microbiome zomwe zimaneneratu kupulumuka. Pa AC-ICAM246, ofufuzawo adayendetsa OS Cox regression model yomwe idasankha zinthu 41 zomwe zili ndi ma coefficients osakhala zero (ogwirizana ndi chiopsezo cha imfa chosiyana), chotchedwa MBR classifiers (Chithunzi 3f).
Mu gulu lophunzitsira ili (ICAM246), chiŵerengero chochepa cha MBR (MBR<0, MBR yotsika) chinagwirizanitsidwa ndi chiopsezo chotsika kwambiri cha imfa (85%). Ofufuza adatsimikiza mgwirizano pakati pa MBR yotsika (chiopsezo) ndi OS yayitali m'magulu awiri odziyimira pawokha (ICAM42 ndi TCGA-COAD). (Chithunzi 3) Kafukufukuyu adawonetsa mgwirizano wamphamvu pakati pa endogastric cocci ndi MBR scores, zomwe zinali zofanana mu chotupa ndi minofu ya m'matumbo yathanzi.

Chithunzi 3. Microbiome mu chotupa ndi minofu yathanzi komanso ubale ndi ICR ndi kupulumuka kwa wodwala.
Mapeto
Njira yogwiritsira ntchito ma multi-omics yomwe yagwiritsidwa ntchito mu kafukufukuyu imalola kuzindikira bwino ndi kusanthula kwa mamolekyu a chitetezo chamthupi mu khansa ya m'matumbo ndipo ikuwonetsa kuyanjana pakati pa microbiome ndi chitetezo chamthupi. Kusanthula kwakuya kwa TCR kwa chotupa ndi minofu yathanzi kwawonetsa kuti zotsatira za ICR zitha kukhala chifukwa cha kuthekera kwake kugwira ma clones a T cell omwe ali ndi chotupa komanso mwina antigen yeniyeni ya chotupa.

Mwa kusanthula kapangidwe ka tizilombo toyambitsa matenda pogwiritsa ntchito njira ya 16S rRNA gene mu zitsanzo za AC-ICAM, gululi linapeza chizindikiro cha tizilombo toyambitsa matenda (MBR risk score) chomwe chili ndi phindu lalikulu lolosera. Ngakhale chizindikirochi chinachokera ku zitsanzo za chotupa, panali mgwirizano wamphamvu pakati pa colorectum wathanzi ndi chiwerengero cha tumor MBR risk score, zomwe zikusonyeza kuti chizindikirochi chikhoza kujambula kapangidwe ka tizilombo toyambitsa matenda m'matumbo mwa odwala. Mwa kuphatikiza ziwerengero za ICR ndi MBR, zinali zotheka kuzindikira ndikutsimikizira biomarker ya ophunzira a multi-omic yomwe imaneneratu kupulumuka kwa odwala omwe ali ndi khansa ya m'matumbo. Deta ya multi-omic ya kafukufukuyu imapereka chidziwitso chomvetsetsa bwino za biology ya khansa ya m'matumbo ndikuthandizira kupeza njira zochiritsira zomwe munthu aliyense angasankhe.

Buku lothandizira:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. Chotupa chophatikizika, immune ndi microbiome atlas ya khansa ya m'matumbo. Nat Med 29, 1273-1286 (2023).