Nat Med | Hanya mai amfani da yawa don zana taswirar ciwon daji da aka haɗa

Nat Med | Tsarin da aka yi amfani da shi wajen tsara taswirar yanayin ciwon daji, garkuwar jiki da ƙwayoyin cuta na hanji ya bayyana hulɗar ƙwayoyin cuta da tsarin garkuwar jiki.
Duk da cewa an yi nazari sosai kan alamun cutar kansar hanji a cikin 'yan shekarun nan, jagororin asibiti na yanzu sun dogara ne kawai akan tsarin metastasis na tumor-lymph node da gano lahani na gyaran DNA (MMR) ko rashin kwanciyar hankali na microsatellite (MSI) (ban da gwajin cututtuka na yau da kullun) don tantance shawarwarin magani. Masu bincike sun lura da rashin alaƙa tsakanin martanin garkuwar jiki bisa ga bayyanar kwayoyin halitta, bayanan ƙwayoyin cuta, da kuma stroma na tumor a cikin ƙungiyar ciwon daji na hanji na Cancer Genome Atlas (TCGA) da kuma rayuwar marasa lafiya.

Yayin da bincike ya ci gaba, an ruwaito cewa halayen adadi na ciwon daji na farko, gami da yanayin ƙwayar cutar kansa, garkuwar jiki, stromal, ko ƙwayoyin cuta na ciwon, suna da alaƙa sosai da sakamakon asibiti, amma har yanzu akwai ƙarancin fahimtar yadda hulɗarsu ke shafar sakamakon marasa lafiya.
Domin tantance alaƙar da ke tsakanin sarkakiyar yanayin halitta da sakamako, ƙungiyar masu bincike daga Cibiyar Binciken Lafiya ta Sidra da ke Qatar kwanan nan ta ƙirƙiro kuma ta tabbatar da wani makin da aka haɗa (mICRoScore) wanda ke gano ƙungiyar marasa lafiya da ke da kyakkyawan ƙimar rayuwa ta hanyar haɗa halayen microbiome da abubuwan da ke hana garkuwar jiki (ICR). Ƙungiyar ta yi cikakken nazarin kwayoyin halitta na sabbin samfuran daskararre daga marasa lafiya 348 da ke da cutar kansar hanji ta farko, gami da jerin RNA na ciwace-ciwacen da suka dace da kyallen hanji, jerin exome gaba ɗaya, mai karɓar ƙwayoyin T-cell mai zurfi da jerin kwayoyin halittar rRNA na ƙwayoyin cuta 16S, wanda aka ƙara masa jerin kwayoyin halittar tumor gaba ɗaya don ƙara bayyana microbiome. An buga binciken a cikin Nature Medicine a matsayin "An haɗa ciwon daji, garkuwar jiki da kuma microbiome atlas na ciwon daji na hanji".

Labarin da aka buga a cikin Magungunan Yanayi

Bayanin AC-ICAM

Masu bincike sun yi amfani da wani dandamali na kwayoyin halitta na orthogonal don yin nazarin samfuran ciwon daji da aka daskare da kuma daidaita kyallen hanji mai lafiya (ƙwayoyin ciwon daji-na al'ada) daga marasa lafiya da aka gano suna da cutar kansar hanji ba tare da maganin tsari ba. Dangane da tsarin tattara bayanai na gaba ɗaya (WES), kula da ingancin bayanai na RNA-seq, da kuma tantance ka'idojin haɗawa, an adana bayanan kwayoyin halitta daga marasa lafiya 348 kuma an yi amfani da su don nazarin ƙasa tare da matsakaicin bin diddigin shekaru 4.6. Ƙungiyar binciken ta sanya wa wannan albarkatu suna Sidra-LUMC AC-ICAM: Taswira da jagora ga hulɗar garkuwar jiki da ciwon daji-microbiome (Hoto na 1).

Rarraba kwayoyin halitta ta amfani da ICR

Ta hanyar kama wani tsari na alamomin kwayoyin halitta na garkuwar jiki don ci gaba da kula da rigakafi na ciwon daji, wanda ake kira da immunoconstant of rejection (ICR), ƙungiyar binciken ta inganta ICR ta hanyar haɗa shi cikin wani kwamitin kwayoyin halitta 20 wanda ya shafi nau'ikan ciwon daji daban-daban, ciki har da melanoma, ciwon mafitsara, da ciwon nono. An kuma danganta ICR da amsawar rigakafi a cikin nau'ikan ciwon daji daban-daban, ciki har da ciwon nono.

Da farko, masu binciken sun tabbatar da sa hannun ICR na ƙungiyar AC-ICAM, ta amfani da hanyar rarraba kwayoyin halitta ta ICR don rarraba ƙungiyar zuwa ƙungiyoyi uku/ƙananan nau'ikan rigakafi: babban ICR (ciwon daji masu zafi), matsakaicin ICR da ƙarancin ICR (ciwon sanyi) (Hoto na 1b). Masu bincike sun bayyana yanayin garkuwar jiki da ke da alaƙa da ƙananan nau'ikan kwayoyin halitta (CMS), rarrabuwar ciwon daji na hanji bisa ga transcriptome. Rukunan CMS sun haɗa da CMS1/immune, CMS2/canonical, CMS3/metabolic da CMS4/mesenchymal. Bincike ya nuna cewa maki na ICR suna da alaƙa mara kyau da wasu hanyoyin ƙwayoyin cutar kansa a cikin dukkan nau'ikan CMS, kuma an lura da alaƙa mai kyau tare da hanyoyin hana rigakafi da hanyoyin da ke da alaƙa da stromal kawai a cikin ciwace-ciwacen CMS4.

A cikin dukkan CMS, yawan ƙwayoyin halitta masu kisa (NK) da ƙwayoyin T sun fi yawa a cikin ƙananan nau'ikan garkuwar jiki masu ƙarfi na ICR, tare da ƙarin bambance-bambance a cikin sauran ƙananan ƙwayoyin leukocyte (Hoto na 1c). Ƙananan nau'ikan garkuwar jiki na ICR suna da OS da PFS daban-daban, tare da ci gaba da ƙaruwa a cikin ICR daga ƙasa zuwa sama (Hoto na 1d), yana tabbatar da rawar da ICR ke takawa a cikin ciwon daji na hanji.

Hoto na 1. Tsarin nazarin AC-ICAM, sa hannun kwayoyin halitta masu alaƙa da garkuwar jiki, nau'ikan garkuwar jiki da ƙwayoyin halitta da kuma rayuwa.
ICR yana kama ƙwayoyin T masu ƙarfi da ƙari a cikin ƙwayoyin cuta
An ruwaito cewa ƙalilan ƙwayoyin T ne kawai ke shiga cikin kyallen ƙari suna da takamaiman ga ƙwayoyin cuta na ƙari (ƙasa da 10%). Saboda haka, yawancin ƙwayoyin T na cikin ƙari ana kiransu ƙwayoyin T masu biye da su (ƙwayoyin T masu biye da su). An lura da mafi ƙarfin alaƙa da adadin ƙwayoyin T na gargajiya tare da TCR masu aiki a cikin ƙananan ƙwayoyin stromal da leukocyte (wanda aka gano ta hanyar RNA-seq), wanda za'a iya amfani da shi don kimanta ƙananan ƙwayoyin T (Hoto na 2a). A cikin ƙungiyoyin ICR (gabaɗaya da rarrabuwar CMS), an lura da mafi girman clonality na immune SEQ TCRs a cikin ƙananan ƙungiyoyin CMS1/immune na ICR-high da CMS (Hoto na 2c), tare da mafi girman rabo na ciwon daji na ICR-high. Ta amfani da dukkan transcriptome (ƙwayoyin halitta 18,270), kwayoyin halittar ICR guda shida (IFNG, STAT1, IRF1, CCL5, GZMA, da CXCL10) suna cikin manyan kwayoyin halitta goma da ke da alaƙa da clonality na immune SEQ na TCR (Hoto na 2d). Tsarin kwayoyin halitta na ImmunoSEQ TCR ya fi ƙarfi da yawancin kwayoyin halittar ICR fiye da alaƙar da aka gani ta amfani da alamun CD8+ masu amsawa ga ciwon daji (Hoto na 2f da 2g). A ƙarshe, binciken da ke sama ya nuna cewa sa hannun ICR ya kama kasancewar ƙwayoyin T masu wadatar da ciwon daji, waɗanda aka ƙara girmansu kuma yana iya bayyana tasirin hasashensa.

Siffa ta 2. Ma'aunin TCR da alaƙa da kwayoyin halittar da ke da alaƙa da garkuwar jiki, nau'ikan garkuwar jiki da ƙwayoyin halitta.
Tsarin microbiome a cikin kyallen lafiya da ciwon daji na hanji
Masu binciken sun yi gwajin rRNA na 16S ta amfani da DNA da aka samo daga ciwon da ya dace da kuma kyallen hanji mai lafiya daga marasa lafiya 246 (Hoto na 3a). Don tabbatarwa, masu binciken sun kuma yi nazarin bayanan jerin kwayoyin halitta na rRNA na 16S daga ƙarin samfuran ciwon daji 42 waɗanda ba su dace da DNA na yau da kullun da ake da su don yin nazari ba. Da farko, masu binciken sun kwatanta yawan flora tsakanin ciwon daji da suka dace da kyallen hanji mai lafiya. An ƙara yawan Clostridium perfringens a cikin ciwon daji idan aka kwatanta da samfuran lafiya (Hoto na 3a-3d). Babu wani bambanci mai mahimmanci a cikin bambancin alpha (bambancin da yawan nau'ikan a cikin samfuri ɗaya) tsakanin ciwon daji da samfuran lafiya, kuma an lura da raguwar bambancin ƙwayoyin cuta a cikin ciwon daji masu yawan ICR idan aka kwatanta da ciwon daji masu ƙarancin ICR.
Domin gano alaƙar da ke tsakanin bayanan ƙwayoyin cuta da sakamakon asibiti, masu binciken sun yi niyyar amfani da bayanan jerin kwayoyin halitta na 16S rRNA don gano siffofin ƙwayoyin cuta waɗanda ke hasashen rayuwa. A AC-ICAM246, masu binciken sun gudanar da samfurin OS Cox regression wanda ya zaɓi siffofi 41 tare da ma'auni marasa sifili (wanda ke da alaƙa da bambancin haɗarin mace-mace), wanda ake kira MBR classifiers (Hoto na 3f).
A cikin wannan rukunin horo (ICAM246), ƙarancin maki na MBR (MBR<0, ƙarancin MBR) yana da alaƙa da ƙarancin haɗarin mutuwa (85%). Masu bincike sun tabbatar da alaƙar da ke tsakanin ƙarancin MBR (haɗari) da tsawaitawar OS a cikin ƙungiyoyi biyu masu zaman kansu waɗanda aka tabbatar da kansu (ICAM42 da TCGA-COAD). (Hoto na 3) Binciken ya nuna alaƙa mai ƙarfi tsakanin ƙimar endogastric cocci da MBR, waɗanda suka yi kama da juna a cikin ciwon daji da kyallen hanji mai lafiya.

Hoto na 3. Kwayoyin cuta a cikin ƙari da kyallen lafiya da alaƙar da ke tsakanin ICR da rayuwar marasa lafiya.
Kammalawa
Hanyar multi-omics da aka yi amfani da ita a cikin wannan binciken tana ba da damar ganowa da kuma yin nazari sosai kan sa hannun kwayoyin halitta na martanin garkuwar jiki a cikin ciwon daji na hanji kuma tana bayyana hulɗar da ke tsakanin microbiome da tsarin garkuwar jiki. Tsarin TCR mai zurfi na ƙari da kyallen lafiya ya nuna cewa tasirin hasashen ICR na iya kasancewa saboda iyawarsa ta kama ƙwayoyin T na musamman na ƙwayoyin T masu wadatar da ƙari da kuma wataƙila na ƙwayoyin T.

Ta hanyar nazarin tsarin ƙwayoyin cuta na ƙari ta amfani da jerin kwayoyin halitta na 16S rRNA a cikin samfuran AC-ICAM, ƙungiyar ta gano sa hannun ƙwayoyin cuta na ƙwayar cuta (maki na haɗarin MBR) tare da ƙimar hasashen mai ƙarfi. Kodayake an samo wannan sa hannun ne daga samfuran ƙari, akwai alaƙa mai ƙarfi tsakanin lafiyayyen colorectum da ƙimar haɗarin MBR na ƙari, yana nuna cewa wannan sa hannun na iya kama tsarin ƙwayoyin cuta na hanji na marasa lafiya. Ta hanyar haɗa maki na ICR da MBR, ya yiwu a gano da kuma tabbatar da alamar ɗalibi mai yawan-omic wanda ke annabta rayuwa a cikin marasa lafiya da ke fama da ciwon hanji. Bayanan bincike na multi-omic na binciken yana ba da hanya don fahimtar ilimin halittar ciwon hanji da kuma taimakawa wajen gano hanyoyin magani na musamman.

Nassoshi:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. Haɗaɗɗen ƙari, rigakafi da microbiome atlas na ciwon daji na hanji. Nat Med 29, 1273-1286 (2023).