Nat Med |Mokhoa oa li-multi-omics oa ho etsa 'mapa oa hlahala e kopaneng

Nat Med |Mokhoa o fapaneng oa ho etsa 'mapa oa hlahala e kopaneng, sebopeho sa 'mele le likokoana-hloko tsa mofetše oa colorectal o senola tšebelisano ea microbiome le sesole sa' mele.
Leha li-biomarker tsa mofets'e oa mantlha oa mofets'e li 'nile tsa ithutoa haholo lilemong tsa morao tjena, litataiso tsa hona joale tsa kliniki li itšetlehile feela ka tumor-lymph node-metastasis staging le ho lemoha mefokolo ea DNA mismatch (MMR) kapa ho se tsitse ha microsatellite (MSI) (ho kenyelletsa tlhahlobo e tloaelehileng ea mafu. ) ho fumana litlhahiso tsa phekolo.Bafuputsi ba hlokometse ho haella ha kamano lipakeng tsa likarabelo tsa 'mele tse thehiloeng ho liphatsa tsa lefutso, li-microbial profiles, le tumor stroma ho Cancer Genome Atlas (TCGA) cohort ea mofetše oa colorectal le ho pholoha ha mokuli.

Ha lipatlisiso li ntse li tsoela pele, litšoaneleho tse ngata tsa mofets'e oa mantlha, ho kenyelletsa lisele tsa mofetše, 'mele oa ho itšireletsa mafung, stromal, kapa likokoana-hloko tsa mofets'e, li tlalehiloe li amana haholo le liphetho tsa bongaka, empa ho ntse ho e-na le kutloisiso e fokolang ea hore na litšebelisano tsa bona li ama liphello tsa mokuli joang. .
Ho arola kamano pakeng tsa ho rarahana ha phenotypic le sephetho, sehlopha sa bafuputsi ba Setsi sa Sidra sa Patlisiso ea Bongaka se Qatar se sa tsoa hlahisa le ho netefatsa lintlha tse kopaneng (mICRoScore) tse khethollang sehlopha sa bakuli ba nang le litekanyetso tse ntle tsa ho phela ka ho kopanya litšobotsi tsa microbiome le ho hana ho itšireletsa ha 'mele. li-constants (ICR).Sehlopha se entse tlhahlobo e felletseng ea lisampole tse ncha tse hatselitsoeng ho tsoa ho bakuli ba 348 ba nang le mofetše oa mantlha oa colorectal, ho kenyeletsoa tatellano ea lihlahala tsa RNA le lisele tse phetseng hantle tsa 'mala, tatellano ea li-exome, receptor e tebileng ea T-cell le tatellano ea liphatsa tsa lefutso tsa 16S tsa baktheria rRNA. tatellano ea liphatsa tsa lefutso ho tsoela pele ho khetholla microbiome.Boithuto bona bo phatlalalitsoe ho Nature Medicine e le "Tumor e kopaneng, atlas ea 'mele ea ho itšireletsa mafung le microbiome ea mofets'e oa colon".

Sehlooho se hatisitsoeng ho Nature Medicine

Tlhaloso ea AC-ICAM

Bafuputsi ba sebelisitse sethala sa orthogonal genomic ho sekaseka lisampole tse ncha tse hoamisitsoeng le ho tsamaisana le lisele tse haufi tsa colon tse phetseng hantle (lipara tse tloaelehileng tsa hlahala) ho tsoa ho bakuli ba nang le tlhahlobo ea nalane ea mofetše oa colon ntle le kalafo ea systemic.E ipapisitse le tatellano ea li-whole-exome (WES), taolo ea boleng ba data ea RNA-seq, le tlhahlobo ea litekanyetso tsa ho kenyelletsa, lintlha tsa genomic tse tsoang ho bakuli ba 348 li ile tsa bolokoa mme tsa sebelisoa bakeng sa tlhahlobo e tlase ka ho latela lilemo tse 4.6.Sehlopha sa lipatlisiso se ile sa reha sesebelisoa sena Sidra-LUMC AC-ICAM: 'Mapa le tataiso ea ho sebelisana ha 'mele oa kankere-microbiome (Setšoantšo sa 1).

Sehlopha sa limolek'hule se sebelisa ICR

Ka ho hapa matšoao a liphatsa tsa lefutso tsa ho itšireletsa mafung bakeng sa ts'ireletso ea mofets'e e tsoelang pele, e bitsoang "immune constant of rejection (ICR), sehlopha sa lipatlisiso se ntlafalitse ICR ka ho e kopanya ka har'a phanele ea liphatsa tsa lefutso tse 20 tse koahelang mefuta e fapaneng ea mofetše, ho kenyeletsoa melanoma, mofets'e oa senya le. kankere ea matsoele.ICR e boetse e amahanngoa le karabelo ea immunotherapy mefuteng e fapaneng ea mofetše, ho kenyeletsoa mofetše oa matsoele.

Taba ea pele, bafuputsi ba netefalitse signature ea ICR ea sehlopha sa AC-ICAM, ba sebelisa mokhoa oa ho arola liphatsa tsa lefutso tsa ICR ho arola sehlopha ka lihlopha tse tharo / li-immune subtypes: ICR e phahameng (lihlahala tse chesang), ICR e bohareng le ICR e tlase (e batang). lihlahala) (Setšoantšo sa 1b).Bafuputsi ba bontšitse tšekamelo ea 'mele ea ho itšireletsa mafung e amanang le tumellano ea limolek'hule subtypes (CMS), sehlopha sa mofetše oa colon o thehiloeng ho transcriptome.mekhahlelo ea CMS e ne e kenyelletsa CMS1/immune, CMS2/canonical, CMS3/metabolic le CMS4/mesenchymal.Litlhahlobo li bonts'itse hore lintlha tsa ICR li ne li hokahane hampe le litsela tse ling tsa lisele tsa mofetše ho li-subtypes tsohle tsa CMS, 'me likhokahano tse ntle le litsela tse amanang le immunosuppressive le tse amanang le stromal li ile tsa bonoa feela lihlahala tsa CMS4.

Ho CMS eohle, bongata ba li-cell killer (NK) cell le T cell subsets li ne li phahame ka ho fetisisa ho ICR e phahameng ea ho itšireletsa mafung, e nang le phapang e kholo ho tse ling tsa leukocyte subsets (Setšoantšo sa 1c) . ho ICR ho tloha tlase ho ea holimo (Setšoantšo sa 1d), ho netefatsa karolo ea pele ea ICR ho mofetše oa colorectal.

Setšoantšo sa 1. Moralo oa ho ithuta oa AC-ICAM, signature ea liphatsa tsa lefutso tse amanang le 'mele, li-immune le molecular subtypes le ho pholoha.
ICR e tšoara lisele tsa T tse matlafalitsoeng, tse holisitsoeng ka bonngoe
Ke lisele tse fokolang feela tsa T tse kenang ka har'a lisele tsa hlahala tse tlalehiloeng e le tse tobileng bakeng sa li-antigen tsa tumor (ka tlase ho 10%).Ka hona, boholo ba lisele tsa T tsa intra-tumor li bitsoa lisele tsa T tse emeng (lisele tsa T tse emeng).Khokahano e matla ka ho fetesisa le palo ea lisele tse tloaelehileng tsa T tse nang le li-TCR tse hlahisang li ile tsa bonoa ka har'a lisele tsa stromal le li-leukocyte subpopulations (tse fumanoeng ke RNA-seq), tse ka sebelisoang ho lekanya li-subpopulations tsa T cell (Setšoantšo sa 2a).Lihlopheng tsa ICR (kakaretso le CMS), palo e phahameng ka ho fetisisa ea li-immune SEQ TCRs e ile ea bonoa ho ICR-high le CMS subtype CMS1 / lihlopha tsa 'mele (Setšoantšo sa 2c), tse nang le karolo e phahameng ka ho fetisisa ea lihlahala tse phahameng tsa ICR.Ho sebelisa transcriptome kaofela (liphatsa tsa lefutso tsa 18,270), liphatsa tsa lefutso tse tšeletseng tsa ICR (IFNG, STAT1, IRF1, CCL5, GZMA, le CXCL10) li ne li le har'a liphatsa tsa lefutso tse leshome tse amanang hantle le TCR immune SEQ clonality (Figure 2d).ImmunoSEQ TCR clonality e hokahane ka matla le liphatsa tsa lefutso tse ngata tsa ICR ho feta likhokahano tse bonoang ho sebelisoa li-CD8+ tse arabelang ka tumor (Setšoantšo sa 2f le 2g).Qetellong, tlhahlobo e kaholimo e fana ka maikutlo a hore tekeno ea ICR e hapa boteng ba lisele tsa T tse ntlafalitsoeng ka mokhoa o kopaneng, 'me e ka hlalosa litlamorao tsa eona tsa pele.

Setšoantšo sa 2. TCR metrics le correlation le liphatsa tsa lefutso tse amanang le 'mele, li-immune le limolek'hule tse nyenyane.
Sebopeho sa Microbiome ka har'a lisele tse phetseng hantle le tsa mofetše oa mala
Bafuputsi ba ile ba etsa tatellano ea 16S rRNA ba sebelisa DNA e nkiloeng ho tsoa hlahala e tšoanang le lisele tse phetseng hantle tsa colon ho tsoa ho bakuli ba 246 (Setšoantšo sa 3a).Bakeng sa netefatso, bafuputsi ba ile ba hlahlobisisa hape data ea tatellano ea liphatsa tsa lefutso tsa 16S rRNA ho tsoa ho lisampole tse ling tse 42 tse neng li sa tsamaisane le DNA e tloaelehileng e fumanehang bakeng sa tlhahlobo.Taba ea pele, bafuputsi ba ile ba bapisa bongata ba limela lipakeng tsa lihlahala tse tšoanang le lisele tse phetseng hantle tsa colon.Clostridium perfringens e ile ea eketseha haholo ka har'a lihlahala ha li bapisoa le lisampole tse phetseng hantle (Setšoantšo sa 3a-3d).Ho ne ho se na phapang e khōlō ho mefuta-futa ea alpha (mefuta-futa le bongata ba mefuta ea sampuli e le 'ngoe) pakeng tsa hlahala le lisampole tse phetseng hantle, 'me ho ile ha hlokomeloa phokotso e itekanetseng ea mefuta-futa ea likokoana-hloko ho lihlahala tse phahameng tsa ICR tse amanang le lihlahala tse tlaase tsa ICR.
Ho bona litloaelano tse amehang lipakeng tsa li-microbial profiles le liphetho tsa bongaka, bafuputsi ba ne ba ikemiselitse ho sebelisa data ea tatellano ea liphatsa tsa lefutso tsa 16S rRNA ho tseba likarolo tsa microbiome tse bolelang esale pele ho pholoha.Ho AC-ICAM246, bafuputsi ba ile ba tsamaisa mokhoa oa ho khutlela morao oa OS Cox o khethileng likarolo tse 41 tse nang le li-coefficients tse se nang zero (tse amanang le kotsi ea ho shoa ha phapang), tse bitsoang MBR classifiers (Figure 3f).
Sehlopheng sena sa koetliso (ICAM246), palo e tlaase ea MBR (MBR <0, MBR e tlaase) e ne e amahanngoa le kotsi e fokolang haholo ea lefu (85%).Bafuputsi ba netefalitse kamano pakeng tsa MBR e tlase (kotsi) le OS ea nako e telele ho lihlopha tse peli tse ikemetseng tse ikemetseng (ICAM42 le TCGA-COAD).(Setšoantšo sa 3) Phuputso e bontšitse kamano e matla pakeng tsa endogastric cocci le lintlha tsa MBR, tse neng li tšoana le hlahala le lisele tse phetseng hantle tsa colon.

Setšoantšo sa 3. Microbiome ka hlahala le lisele tse phetseng hantle le kamano le ICR le ho phela ha mokuli.
Qetello
Mokhoa oa li-multi-omics o sebelisitsoeng thutong ena o thusa ho lemoha le ho hlahloba ka botlalo pontšo ea molek'hule ea karabelo ea 'mele ea ho itšireletsa mafung ho mofetše oa colorectal le ho senola tšebelisano pakeng tsa microbiome le sesole sa' mele.Tatelano e tebileng ea TCR ea hlahala le lisele tse phetseng hantle li senotse hore phello ea ICR e kanna ea ba ka lebaka la bokhoni ba eona ba ho ts'oara li-cell clones tse ntlafetseng tsa tumor-antigen-specific T.

Ka ho hlahloba sebopeho sa tumor microbiome se sebelisa 16S rRNA gene sequencing ka lisampole tsa AC-ICAM, sehlopha se ile sa tsebahatsa signature ea microbiome (sekolo sa kotsi ea MBR) e nang le boleng bo matla ba prognoza.Leha tekeno ena e nkiloe ho lisampole tsa hlahala, ho bile le kamano e matla lipakeng tsa kotsi e phetseng hantle ea colorectum le tumor MBR, ho fana ka maikutlo a hore tekeno ena e ka ts'oara sebopeho sa bakuli sa gut microbiome.Ka ho kopanya lintlha tsa ICR le MBR, ho ne ho ka khoneha ho khetholla le ho netefatsa biomarker ea liithuti tse ngata tse bolelang esale pele ho pholoha ho bakuli ba nang le mofetše oa mala.Lethathamo la data la thuto e ngata le fana ka sesebelisoa sa ho utloisisa biology ea mofetše oa mala le ho thusa ho fumana mekhoa ea kalafo ea motho ka mong.

Referense:
Roelands, J., Kuppen, PJK, Ahmed, EI et al.Sehlahala se kopantsoeng, 'mele oa ho itšireletsa mafung le microbiome atlas ea mofetše oa colon.Nat Med 29, 1273–1286 (2023).