nkhani

Immunotherapy yabweretsa kusintha kosinthika pakuchiza zotupa zowopsa, komabe pali odwala ena omwe sangapindule. Chifukwa chake, ma biomarker oyenerera amafunikira mwachangu pamagwiritsidwe azachipatala kuti athe kuneneratu za mphamvu ya immunotherapy, kuti apititse patsogolo mphamvu ndikupewa poizoni wosafunikira.

FDA idavomereza biomarkers

PD-L1 mawu. Kuwunika kwa mafotokozedwe a PD-L1 pogwiritsa ntchito immunohistochemistry (IHC) kumapereka chiwerengero cha chotupa (TPS), chomwe ndi kuchuluka kwa maselo otupa omwe ali ndi nembanemba pang'ono kapena kwathunthu amphamvu zilizonse zama cell chotupa. M'mayesero azachipatala, kuyezetsa uku kumakhala ngati kuyesa kothandizira pochiza khansa ya m'mapapo yosakhala yaying'ono ya cell (NSCLC) yokhala ndi pembrolizumab. Ngati TPS ya chitsanzo ndi ≥ 1%, mawu a PD-L1 amaganiziridwa; TPS ≥ 50% imasonyeza kufotokoza kwakukulu kwa PD-L1. Pachiyeso choyambirira cha Phase 1 (KEYNOTE-001), kuyankha kwa odwala mu PD-L1 TPS> 50% kagulu kamene amagwiritsa ntchito pembrolizumab kunali 45.2%, ngakhale mosasamala kanthu za TPS, kuyankha kwa odwala onse omwe amalandila chithandizo cha chitetezo cha mthupi (ICI) chinali 19.4%. Mayesero otsatirawa a gawo la 2/3 (KEYNOTE-024) adapatsidwa mwachisawawa odwala omwe ali ndi PD-L1 TPS> 50% kuti alandire pembrolizumab ndi chemotherapy wamba, ndipo zotsatira zake zidawonetsa kusintha kwakukulu pakupulumuka kwathunthu (OS) kwa odwala omwe amalandira chithandizo cha pembrolizumab.

Komabe, kugwiritsa ntchito PD-L1 pakulosera mayankho a ICI kumachepa ndi zinthu zosiyanasiyana. Choyamba, mulingo woyenera kwambiri wa mitundu yosiyanasiyana ya khansa umasiyanasiyana. Mwachitsanzo, Pabolizumab angagwiritsidwe ntchito pamene chotupa PD-L1 kufotokoza odwala khansa chapamimba, khansa esophageal, khansa ya chikhodzodzo ndi khansa ya m'mapapo ndi 1%, 10% ndi 50% motero. Kachiwiri, kuwunika kuchuluka kwa ma cell a PD-L1 kumasiyanasiyana kutengera mtundu wa khansa. Mwachitsanzo, chithandizo cha squamous cell carcinoma yobwerezabwereza kapena ya metastatic ya mutu ndi khosi ingasankhe kugwiritsa ntchito njira ina yovomerezeka ya FDA, Comprehensive Positive Score (CPS). Chachitatu, palibe pafupifupi kulumikizana pakati pa PD-L1 m'matenda osiyanasiyana a khansa ndi kuyankha kwa ICI, zomwe zikuwonetsa kuti chotupacho chingakhale chofunikira kwambiri pakulosera za ICI biomarkers. Mwachitsanzo, molingana ndi zotsatira za mayeso a CheckMate-067, mtengo wolosera wa PD-L1 mu melanoma ndi 45% yokha. Pomaliza, kafukufuku wambiri wapeza kuti mawu a PD-L1 ndi osagwirizana pa zotupa zosiyanasiyana za chotupa mwa wodwala m'modzi, ngakhale mkati mwa chotupa chomwecho. Mwachidule, ngakhale mayesero oyambilira azachipatala a NSCLC adalimbikitsa kafukufuku wamafotokozedwe a PD-L1 ngati cholosera cholosera, momwe chithandizo chake chamankhwala mumitundu yosiyanasiyana ya khansa sichikudziwika.

Katundu wosinthika wa chotupa. Chotupa cha Mutation Burden (TMB) chagwiritsidwa ntchito ngati chizindikiro china cha chotupa cha immunogenicity. Malinga ndi zotsatira za mayeso azachipatala a KEYNOTE-158, mwa mitundu 10 ya zotupa zolimba zolimba zomwe zimathandizidwa ndi pembrolizumab, odwala omwe ali ndi masinthidwe osachepera 10 pa megabase (high TMB) anali ndi chiwopsezo chachikulu choyankha kuposa omwe ali ndi TMB yotsika. Ndizofunikira kudziwa kuti mu kafukufukuyu, TMB inali yolosera za PFS, koma sinathe kulosera OS.

Kuyankha kwa chitetezo chamthupi kumayendetsedwa makamaka ndi kuzindikira kwa T cell kwa ma antigen atsopano. The immunogenicity kugwirizana ndi apamwamba TMB komanso zimadalira zinthu zosiyanasiyana, kuphatikizapo chotupa neoantigen anapereka chotupa; Chitetezo cha mthupi chimazindikira ma neoantigens chotupa; Kuthekera kwa wolandirayo kuyambitsa mayankho okhudzana ndi antigen. Mwachitsanzo, deta imasonyeza kuti zotupa zomwe zimalowetsa kwambiri m'maselo ena a chitetezo cha mthupi zimatha kukhala ndi zoletsa zoletsa T cell (Treg) clone amplification. Kuphatikiza apo, mtundu wa TMB ukhoza kusiyana ndi kuthekera kwa TMB neoantigens, popeza malo enieni a masinthidwe amakhalanso ndi gawo lalikulu; Kusintha komwe kumayimira njira zosiyanasiyana zowonetsera ma antigen kumatha kukhudza kuwonetsera (kapena kusawonetsa) kwa ma antigen atsopano ku chitetezo chamthupi, kuwonetsa kuti mawonekedwe a chotupa komanso chitetezo chamthupi ayenera kukhala osasinthasintha kuti apange mayankho abwino a ICI.

Pakali pano, TMB imayesedwa kudzera m'mibadwo yotsatira (NGS), yomwe imatha kusiyana pakati pa mabungwe osiyanasiyana (mkati) kapena nsanja zamalonda zomwe zimagwiritsidwa ntchito. NGS imaphatikizapo kutsatizana kwa ma exome (WES), kutsatizana kwa ma genome onse, ndikutsatizana komwe kumayang'aniridwa, komwe kumatha kupezedwa kuchokera ku minofu ya chotupa ndikuzungulira chotupa cha DNA (ctDNA). Ndikoyenera kudziwa kuti mitundu yosiyanasiyana ya zotupa zimakhala ndi TMB yambiri, zotupa za immunogenic monga melanoma, NSCLC, ndi squamous cell carcinoma zomwe zimakhala ndi TMB zapamwamba kwambiri. Mofananamo, njira zodziwira zopangidwira mitundu yosiyanasiyana ya chotupa zimakhala ndi matanthauzidwe osiyanasiyana a TMB threshold values. Pakufufuza kwa NSCLC, melanoma, urothelial carcinoma, ndi khansa yaing’ono ya m’mapapo, njira zodziŵira zimenezi zimagwiritsa ntchito njira zowunikira zosiyanasiyana (monga WES kapena PCR kuzindikira manambala okhudzana ndi jini) ndi ma thresholds (TMB high or TMB low).

Ma Microsatellites ndi osakhazikika kwambiri. Microsatellite yosakhazikika kwambiri (MSI-H), monga choyimira cha khansa ya pan pa kuyankha kwa ICI, ili ndi ntchito yabwino kwambiri yolosera zamphamvu za ICI m'makhansa osiyanasiyana. MSI-H ndi chifukwa cha zolakwika zowonongeka (dMMR), zomwe zimapangitsa kuti pakhale kusintha kwakukulu, makamaka m'madera a microsatellites, zomwe zimapangitsa kuti pakhale ma antigen ambiri atsopano ndipo potsirizira pake amachititsa kuti chitetezo cha mthupi chitetezeke. Chifukwa cha kuchuluka kwa masinthidwe olemedwa ndi dMMR, zotupa za MSI-H zitha kuonedwa ngati mtundu wa chotupa chachikulu cholemetsa (TMB). Kutengera zotsatira za mayeso azachipatala a KEYNOTE-164 ndi KEYNOTE-158, a FDA avomereza pembrolizumab pochiza zotupa za MSI-H kapena dMMR. Awa ndi amodzi mwamankhwala oyamba a khansa yapa pan kuvomerezedwa ndi FDA motsogozedwa ndi chotupa biology osati histology.

Ngakhale kupambana kwakukulu, palinso zovuta zomwe muyenera kuzidziwa mukamagwiritsa ntchito MSI. Mwachitsanzo, mpaka 50% ya odwala khansa ya colorectal dMMR alibe yankho ku chithandizo cha ICI, kuwonetsa kufunikira kwa zinthu zina pakulosera kuyankha. Zinthu zina zamkati za zotupa zomwe sizingawunikidwe ndi nsanja zomwe zikuzindikirika zitha kukhala zomwe zikuthandizira. Mwachitsanzo, pakhala malipoti oti odwala omwe ali ndi masinthidwe amtundu omwe amasunga ma subunits ofunikira a polymerase delta (POLD) kapena polymerase ε (POLE) m'chigawo cha DNA alibe kukhulupirika kobwerezabwereza ndipo amawonetsa "kusintha kwakukulu" phenotype mu zotupa zawo. Zina mwa zotupazi zachulukitsa kwambiri kusakhazikika kwa microsatellite (kotero kukhala a MSI-H), koma mapuloteni okonza zolakwika sakusowa (chifukwa chake osati dMMR).

Kuonjezera apo, mofanana ndi TMB, MSI-H imakhudzidwanso ndi mitundu yatsopano ya antigen yomwe imapangidwa ndi kusakhazikika kwa microsatellite, kuzindikira kwamtundu wa mitundu yatsopano ya antigen, komanso kuyankha kwa chitetezo cha mthupi. Ngakhale muzotupa zamtundu wa MSI-H, kuchuluka kwa masinthidwe a nucleotide amodzi kwadziwika ngati kusintha kwa anthu (osakhala oyendetsa masinthidwe). Choncho, kudalira kokha chiwerengero cha ma microsatellites odziwika mu chotupa sikokwanira; Mtundu weniweni wa masinthidwe (wodziwika kudzera m'mafayilo ena osinthika) ukhoza kupititsa patsogolo magwiridwe antchito a biomarker iyi. Kuphatikiza apo, ndi gawo laling'ono chabe la odwala khansa omwe ali m'matumbo a MSI-H, zomwe zikuwonetsa kufunikira kwapano kwa ma biomarker omwe amagwiritsidwa ntchito kwambiri. Chifukwa chake, kuzindikira ma biomarker ena ogwira mtima kuti athe kuneneratu zogwira mtima ndikuwongolera kasamalidwe ka odwala kumakhalabe gawo lofunikira lofufuzira.

Kafukufuku wokhazikitsidwa ndi bungwe la biomarker

Popeza kuti njira ya ICI ndikusintha kuponderezana kwa maselo a chitetezo chamthupi m'malo molunjika mwachindunji njira zamkati zama cell chotupa, kafukufuku wopitilira ayenera kuyang'ana kwambiri pakuwunika momwe chotupa chikukula komanso kulumikizana pakati pa maselo a chotupa ndi ma cell a chitetezo chamthupi, zomwe zingathandize kuwunikira zomwe zimakhudza kuyankha kwa ICI. Magulu ambiri ofufuza aphunzira chotupa kapena chitetezo chamthupi chamitundu ina, monga chotupa ndi mawonekedwe amtundu wa chitetezo chamthupi, kuchepa kwa antigen, kapena malo oteteza chitetezo chamthupi ambiri (monga ma tertiary lymphoid structures), omwe amatha kulosera mayankho ku immunotherapy.

Ofufuzawo adagwiritsa ntchito NGS kutsata chotupacho komanso chitetezo chamthupi komanso zolemba zamatenda a odwala asanalandire chithandizo cha ICI komanso pambuyo pake, ndikuwunikanso kusanthula kwapamalo. Pogwiritsa ntchito zitsanzo zambiri zophatikizika, zophatikizidwa ndi njira monga kutsatizana kwa selo limodzi ndi kulingalira kwa malo, kapena ma multi omics, luso lolosera za zotsatira za chithandizo cha ICI zakhala zikuyenda bwino. Kuphatikiza apo, njira yokwanira yowunikira zizindikiro za chitetezo chamthupi chotupa komanso mawonekedwe a chotupa chamkati chawonetsanso luso lolosera mwamphamvu. Mwachitsanzo, njira yotsatizana ya batch yomwe nthawi imodzi imayesa chotupa ndi mawonekedwe a chitetezo chamthupi ndi yabwino kuposa kusanthula kumodzi. Zotsatirazi zikuwonetsa kufunikira kofananiza ukadaulo wa ICI mwatsatanetsatane, kuphatikiza kuphatikizira zowunikira za mphamvu ya chitetezo chamthupi, mawonekedwe a chotupa chamkati, ndi zigawo zachitetezo cha chotupa mwa wodwala aliyense kuti adziwike bwino omwe odwala angayankhe ku immunotherapy.

Poganizira zovuta zophatikizira chotupa ndi zinthu zomwe zimachitikira pakufufuza kwa biomarker, komanso kufunikira kophatikizana kwa nthawi yayitali kwa chitetezo chamthupi, anthu ayamba kuwunika ma biomarker pogwiritsa ntchito makina apakompyuta komanso kuphunzira makina. Pakadali pano, zopindulitsa zina zazikulu zachitika pankhaniyi, zomwe zikuwonetsa tsogolo la oncology yothandizidwa ndi kuphunzira pamakina.

Mavuto omwe amakumana ndi ma biomarkers a minofu

Zochepa za njira zowunikira. Ma biomarker ena ofunikira amachita bwino m'mitundu ina ya chotupa, koma osati m'mitundu ina. Ngakhale mawonekedwe amtundu wa chotupa ali ndi mphamvu zolosera zamphamvu kuposa TMB ndi ena, sangathe kugwiritsidwa ntchito pozindikira zotupa zonse. Pakafukufuku wokhudza odwala a NSCLC, mawonekedwe osinthika a jini adapezeka kuti amalosera kwambiri za ICI yothandiza kwambiri kuposa TMB yapamwamba (≥ 10), koma opitilira theka la odwala sanathe kuzindikira mawonekedwe a gene.

Chotupa heterogeneity. Tizilombo totengera njira ya biomarker timangowonetsa pamalo amodzi okha chotupa, zomwe zikutanthauza kuti kuwunika kwa ziwalo zinazake zotupa sikungawonetse molondola mawonekedwe a zotupa zonse mwa wodwalayo. Mwachitsanzo, kafukufuku wapeza kusiyanasiyana kwa mawu a PD-L1 pakati ndi mkati mwa zotupa, ndipo zovuta zofananira zilipo ndi zolembera zina.

Chifukwa cha zovuta zamakina achilengedwe, ma biomarker ambiri omwe amagwiritsidwa ntchito kale atha kukhala osavuta. Kuphatikiza apo, ma cell a chotupa microenvironment (TME) nthawi zambiri amakhala oyenda, kotero kuyanjana komwe kumawonetsedwa pakuwunika kwa malo sikungawonetse kuyanjana kowona pakati pa maselo otupa ndi maselo oteteza thupi. Ngakhale ma biomarkers atha kuyimira chotupa chonsecho panthawi yake, zolingazi zitha kukopeka ndikusintha pakapita nthawi, zomwe zikuwonetsa kuti chithunzi chimodzi panthawi imodzi sichingawonetse kusintha kwamphamvu.

Wodwala heterogeneity. Ngakhale kusintha kodziwika kwa majini okhudzana ndi kukana kwa ICI kuzindikirika, odwala ena omwe ali ndi zizindikiro zodziwikiratu zodziwikiratu amatha kupindula, mwina chifukwa cha kusiyanasiyana kwa mamolekyu ndi/kapena chitetezo chamthupi mkati mwa chotupacho komanso malo osiyanasiyana otupa. Mwachitsanzo, kusowa kwa β2-microglobulin (B2M) kungasonyeze kukana kwatsopano kapena kupezedwa kwa mankhwala, koma chifukwa cha kusiyana kwa kusowa kwa B2M pakati pa anthu ndi mkati mwa zotupa, komanso kugwirizana kwa njira zowonetsera chitetezo cha mthupi mwa odwalawa, kusowa kwa B2M sikungathe kulosera mwamphamvu kukana kwa mankhwala. Chifukwa chake, ngakhale pali kuchepa kwa B2M, odwala amatha kupindulabe ndi chithandizo cha ICI.

Zolemba zautali za bungwe
Mafotokozedwe a biomarkers angasinthe pakapita nthawi komanso ndi zotsatira za chithandizo. Kuwunika kosasunthika komanso kumodzi kwa zotupa ndi immunobiology kumatha kunyalanyaza kusintha kumeneku, ndipo kusintha kwa chotupa cha TME ndi milingo yoyankhira chitetezo chamthupi kungathenso kunyalanyazidwa. Kafukufuku wambiri wasonyeza kuti kupeza zitsanzo musanayambe komanso panthawi ya chithandizo kumatha kuzindikira molondola kusintha kokhudzana ndi chithandizo cha ICI. Izi zikuwonetsa kufunikira kwa kuwunika kwamphamvu kwa biomarker.

Zolemba zamagazi zotengera magazi
Ubwino wowunika magazi ndi kuthekera kwake kuyesa zotupa zonse za chotupa, kuwonetsa mawerengedwe apakati m'malo mowerengera malo enieni, kupangitsa kuti ikhale yoyenera kuwunika kusintha kwamphamvu kokhudzana ndi chithandizo. Zotsatira zambiri za kafukufuku wasonyeza kuti kugwiritsa ntchito chotupa DNA (ctDNA) kapena circulating chotupa maselo (CTC) kuti aone yochepa residual matenda (MRD) angatsogolere zisankho mankhwala, koma mayesowa ali ndi zambiri zokhudza kulosera ngati odwala angapindule ndi immunotherapies monga ICI. Chifukwa chake, kuyezetsa kwa ctDNA kuyenera kuphatikizidwa ndi njira zina zoyezera kuyambika kwa chitetezo chamthupi kapena mphamvu ya chitetezo chamthupi. Pachifukwa ichi, kupita patsogolo kwapangidwa mu immunophenotyping ya zotumphukira magazi mononuclear maselo (PBMCs) ndi proteomic kusanthula ma vesicles extracellular ndi plasma. Mwachitsanzo, peripheral immune cell subtypes (monga CD8 + T cells), kufotokoza kwakukulu kwa mamolekyu a chitetezo cha mthupi (monga PD1 pa maselo a CD8 + T), ndi mapuloteni okwera kwambiri a plasma (monga CXCL8, CXCL10, IL-6, IL-10, PRAP1, ndi VEGDNA zowonjezera zowonjezera bio). Ubwino wa njira zatsopanozi ndikuti amatha kuyesa kusintha kwa chotupacho (mofanana ndi kusintha komwe kumapezeka ndi ctDNA) komanso kuwululira kusintha kwa chitetezo chamthupi cha wodwalayo.

Ma Radiomics
Zomwe zimalosera zachidziwitso chazithunzi zimatha kuthana bwino ndi malire a sampuli za biomarker ndi biopsy, ndipo zimatha kuyang'ana chotupa chonsecho komanso malo ena a metastatic nthawi iliyonse. Chifukwa chake, atha kukhala gawo lofunikira la ma biomarker osasokoneza mtsogolo. Delta radiomics imatha kuwerengera mochulukira zosintha zamitundu ingapo ya chotupa (monga kukula kwa chotupa) panthawi zosiyanasiyana, monga isanachitike komanso pambuyo pa chithandizo cha ICI, panthawi ya chithandizo, komanso kutsatira. Ma radiomics a Delta sangangodziwiratu kuyankha koyamba kapena kusapezeka kwa chithandizo choyambirira, komanso kuzindikira kukana kwa ICI munthawi yeniyeni ndikuwunika kubwereza kulikonse pambuyo pakukhululukidwa kwathunthu. Chithunzi chojambula chomwe chimapangidwa kudzera muukadaulo wophunzirira makina ndichabwino kwambiri kuposa mulingo wamba wa RECIST polosera kuyankha kwamankhwala ndi zovuta zomwe zingachitike. Kafukufuku waposachedwa akuwonetsa kuti mitundu ya radiomics iyi ili ndi malo opindika (AUC) mpaka 0.8 mpaka 0.92 kulosera kuyankha kwa chitetezo chamthupi.

Ubwino wina wa ma radiomics ndi kuthekera kwake kuzindikira molondola kupita patsogolo kwa pseudo. Mtundu wa radiomics wopangidwa kudzera mu kuphunzira kwamakina ungathe kusiyanitsa bwino pakati pa kupita patsogolo koona ndi kwabodza poyesanso deta ya CT kapena PET pachotupa chilichonse, kuphatikiza zinthu monga mawonekedwe, kulimba, ndi kapangidwe kake, ndi AUC ya 0.79. Ma radiomics awa angagwiritsidwe ntchito mtsogolomo kuti apewe kutha msanga kwa chithandizo chifukwa cha kusaganiza bwino za kukula kwa matenda.

Intestinal microbiota
Ma biomarkers a gut microbiota akuyembekezeka kulosera kuyankha kwa ICI. Kafukufuku wambiri wasonyeza kuti matumbo a microbiota amalumikizana kwambiri ndi kuyankha kwa mitundu yosiyanasiyana ya khansa ku chithandizo cha ICI. Mwachitsanzo, kwa odwala khansa ya melanoma ndi chiwindi, kuchuluka kwa mabakiteriya a Ruminococcaceae kumalumikizidwa ndi kuyankha kwa PD-1 immunotherapy. Kulemera kwa Akkermansia muciniphila ndikofala kwa odwala khansa ya chiwindi, khansa ya m'mapapo, kapena renal cell carcinoma, omwe amalabadira chithandizo cha ICI.

Kuphatikiza apo, makina atsopano ophunzirira makina amatha kukhala odziyimira pawokha pamitundu yotupa ndikuphatikiza mtundu wina wa bakiteriya m'matumbo ndi kuyankha kwachire kwa immunotherapy. Kafukufuku wina wawonetsanso gawo lomwe magulu a bakiteriya amatenga nawo gawo pakuwongolera chitetezo chamthupi, ndikuwunikanso momwe angapewere kapena kulimbikitsa chitetezo chamthupi ku maselo a khansa.

Neoadjuvant therapy
Kuwunika kwamphamvu kwa biology ya chotupa kumatha kuwongolera njira zochiritsira zamankhwala. Mayesero a Neoadjuvant Therapy amatha kuwunika momwe achire amachiritsira kudzera pakukhululukidwa kwa ma pathological mu zitsanzo za opaleshoni. Pochiza melanoma, kuyankha koyambirira kwa pathological (MPR) kumalumikizidwa ndi kuchuluka kwa kupulumuka kwaulere. Mu kuyesa kwa PRADO, ochita kafukufuku amawona njira zotsatila zachipatala, monga opaleshoni ndi / kapena chithandizo cha adjuvant, malinga ndi deta yachikhululukiro cha odwala.

Mwa mitundu yosiyanasiyana ya khansa, njira zingapo zatsopano zothandizira adjuvant akadalibe kufananiza. Choncho, kusankha pakati pa immunotherapy monotherapy kapena kuphatikiza mankhwala nthawi zambiri amasankhidwa pamodzi ndi dokotala wopezekapo ndi wodwalayo. Pakadali pano, ochita kafukufuku apanga gawo la interferon gamma (IFN gamma) lomwe lili ndi majini 10 ngati biomarker yolosera kukhululukidwa kwa melanoma pambuyo pa neoadjuvant therapy. Adaphatikizanso izi mu algorithm kuti asankhe odwala omwe ali ndi mayankho amphamvu kapena ofooka pamankhwala a neoadjuvant. Mu kafukufuku wotsatira wotchedwa DONIMI, ochita kafukufuku adagwiritsa ntchito chiwerengerochi, kuphatikizapo kusanthula kovuta kwambiri, osati kungodziwiratu momwe angayankhire chithandizo chamankhwala, komanso kuti adziwe kuti ndi gawo liti lachitatu la odwala melanoma omwe amafunikira kuwonjezera kwa histone deacetylase inhibitors (HDACi) kuti apititse patsogolo kuyankha kwa mankhwala a neoadjuvant ICI.

Chotupa chitsanzo chochokera kwa odwala
Mitundu ya zotupa za in vitro imatha kulosera mayankho enieni a odwala. Mosiyana ndi nsanja ya in vitro yomwe imagwiritsidwa ntchito posanthula kuchuluka kwa ma hematological malignancies, zotupa zolimba zimakumana ndi zovuta zazikulu chifukwa cha mawonekedwe ake apadera a chotupa komanso kulumikizana kwa chitetezo chamthupi. Chikhalidwe chosavuta cha cell chotupa sichingathe kutengera zinthu zovuta izi. Pamenepa, chotupa ngati ziwalo kapena chiwalo tchipisi chochokera kwa odwala akhoza kubweza zofooka structural izi, monga iwo akhoza kusunga chotupa maselo oyambirira ndi kutsanzira kuyanjana ndi lymphoid ndi myeloid maselo chitetezo cha m'thupi kuwunika mayankho a ICI m'njira wodwala, potero kubereka molondola kwambiri mbali zachilengedwe m'malo enieni adimensional atatu.

Maphunziro angapo opambana ku China ndi United States atengera mtundu watsopano wa kukhulupirika wapamwamba wamitundu itatu mu vitro chotupa. Zotsatira zikuwonetsa kuti mitundu iyi imatha kuneneratu bwino momwe khansa ya m'mapapo, khansa ya m'matumbo, khansa ya m'mawere, khansa ya melanoma ndi zotupa zina ku ICI. Izi zimayala maziko otsimikiziranso ndikuwongolera magwiridwe antchito amitundu iyi.