{"id":1784,"date":"2019-10-28T13:54:16","date_gmt":"2019-10-28T12:54:16","guid":{"rendered":"https:\/\/www.newslab.sk\/2019\/10\/28\/protinadorova-reakcia-v-mikroprostredi-kolorektalneho-karcinomu\/"},"modified":"2019-11-04T14:30:54","modified_gmt":"2019-11-04T13:30:54","slug":"protinadorova-reakcia-v-mikroprostredi-kolorektalneho-karcinomu","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/protinadorova-reakcia-v-mikroprostredi-kolorektalneho-karcinomu\/","title":{"rendered":"An antitumoral reaction in micro-environment of colorectal cancer"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

 <\/p>\n

\u00davod<\/strong><\/p>\n

Zhubn\u00e9 n\u00e1dory hrub\u00e9ho \u010dreva patria medzi najpo\u010detnej\u0161ie mal\u00edgne ochorenia vo vyspel\u00fdch \u0161t\u00e1toch sveta. Slovensk\u00e1 republika sa nach\u00e1dza na jednom z popredn\u00fdch miest v celosvetovom rebr\u00ed\u010dku, v Eur\u00f3pe m\u00e1 po Ma\u010farsku a N\u00f3rsku tretiu najvy\u0161\u0161iu incidenciu a je na prvom mieste v mortalite na kolorekt\u00e1lny karcin\u00f3m(1). Na vzniku kolorekt\u00e1lneho karcin\u00f3mu sa podie\u013eaj\u00fa environment\u00e1lne aj genetick\u00e9 faktory. N\u00e1dorov\u00e1 transform\u00e1cia je v\u00fdsledkom postupn\u00e9ho hromadenia genetick\u00fdch a epigenetick\u00fdch zmien, ktor\u00e9 ved\u00fa k transform\u00e1cii povrchov\u00e9ho epitelu hrub\u00e9ho \u010dreva a ovplyv\u0148uj\u00fa jeho biologick\u00e9 spr\u00e1vanie vr\u00e1tane mal\u00edgneho potenci\u00e1lu. Sol\u00eddne tumory vr\u00e1tane n\u00e1dorov hrub\u00e9ho \u010dreva s\u00fa \u010dasto infiltrovan\u00e9 bunkami imunitn\u00e9ho syst\u00e9mu. Za sp\u00fa\u0161\u0165anie imunitnej
\nodpovede zodpovedaj\u00fa aj antig\u00e9ny vzniknut\u00e9 v procese n\u00e1dorovej transform\u00e1cie hromaden\u00edm bunkov\u00fdch mut\u00e1ci\u00ed, tzv. n\u00e1dorov\u00e9 neoantig\u00e9ny. Vplyv protin\u00e1dorov\u00e9ho imunitn\u00e9ho
\nmikroprostredia na progn\u00f3zu n\u00e1dorov je v s\u00fa\u010dasnosti predmetom \u0161t\u00fadia mnoh\u00fdch vedeck\u00fdch pr\u00e1c. Ukazuje sa, \u017ee pr\u00e1ve mikroprostredie transformovan\u00fdch n\u00e1dorov\u00fdch buniek m\u00e1 v\u00fdznam ako prognostick\u00fd faktor a podie\u013ea sa na karcinogen\u00e9ze, a to v \u0161t\u00e1diu inici\u00e1cie aj progresie n\u00e1dorov\u00e9ho rastu(2,3).<\/p>\n

Za norm\u00e1lnych okolnost\u00ed sa imunitn\u00fd syst\u00e9m sna\u017e\u00ed potla\u010di\u0165 n\u00e1dorov\u00fa progresiu bu\u010f zni\u010den\u00edm n\u00e1dorov\u00fdch buniek, alebo inhib\u00edciou ich rastu. Na druhej strane m\u00f4\u017ee imunitn\u00fd
\nsyst\u00e9m podpori\u0165 aj n\u00e1dorov\u00fa progresiu vyselektovan\u00edm rezistentn\u00fdch n\u00e1dorov\u00fdch buniek alebo sa paradoxne podie\u013ea na vytvoren\u00ed imunosupres\u00edvn\u00e9ho n\u00e1dorov\u00e9ho mikroprostredia.
\nPr\u00e1ve schopnos\u0165 n\u00e1dorov\u00fdch buniek kontrolova\u0165 imunitn\u00fd syst\u00e9m a vznik imunitnej rezistencie umo\u017e\u0148uje n\u00e1dorov\u00fdm bunk\u00e1m unikn\u00fa\u0165 spod kontroly a podie\u013ea sa na progresii
\nn\u00e1dorovej choroby(2,4). Cie\u013eom predlo\u017eenej \u0161t\u00fadie je zhodnoti\u0165 aktiv\u00e1ciu imunitn\u00e9ho syst\u00e9mu v n\u00e1doroch hrub\u00e9ho \u010dreva v z\u00e1vislosti od stup\u0148a diferenci\u00e1cie n\u00e1doru a v porovnan\u00ed s okolit\u00fdm n\u00e1dorovo nepostihnut\u00fdm tkanivom hrub\u00e9ho \u010dreva.<\/p>\n

Materi\u00e1ly a met\u00f3dy<\/strong><\/p>\n

Analyzovali sme arch\u00edvne tkanivov\u00e9 vzorky n\u00e1dorov hrub\u00e9ho \u010dreva fixovan\u00e9 formal\u00ednom a zaliate v paraf\u00edne, poch\u00e1dzaj\u00face z terapeutick\u00fdch a diagnostick\u00fdch bioptick\u00fdch odberov
\na archivovan\u00e9 v \u00dastave patologickej anat\u00f3mie LF UK v Bratislave. Vzorky boli histopatologicky pos\u00faden\u00e9 a bola stanoven\u00e1 patologick\u00e1 diagn\u00f3za v zmysle platn\u00fdch krit\u00e9ri\u00ed WHO.
\nZ\u00e1kladn\u00fd s\u00fabor tvorilo 23 pr\u00edpadov kolorekt\u00e1lneho karcin\u00f3mu, z toho 4 pr\u00edpady dobre diferencovan\u00e9ho (G1), 12 pr\u00edpadov stredne diferencovan\u00e9ho (G2) a 3 pr\u00edpady n\u00edzkodiferencovan\u00e9ho (G3) adenokarcin\u00f3mu a 4 pr\u00edpady hlienotvorn\u00e9ho adenokarcin\u00f3mu. Samostatne sme hodnotili miesta s n\u00e1dorov\u00fdm rastom a okolit\u00e9 tkanivo nepostihnut\u00e9 n\u00e1dorom.
\nHodnotili sme infiltr\u00e1ciu tkaniva z\u00e1palov\u00fdmi bunkami so zameran\u00edm na cytotoxick\u00e9 T-lymfocyty (CD8+), pomocn\u00e9 T-lymfocyty (CD4+) a histiocyty (CD68+). Ich pr\u00edtomnos\u0165 bola hodnoten\u00e1
\nimunohistochemicky; v kr\u00e1tkosti odparaf\u00ednovan\u00e9 prepar\u00e1ty boli prepl\u00e1chnut\u00e9 5 min\u00fat v PBS (vo fyziologickom so\u013enom roztoku pufrovanom fosf\u00e1tmi s 10 mM, pH 7,4). Tkanivov\u00e9 epitopy boli n\u00e1sledne demaskovan\u00e9 procesom revitaliz\u00e1cie s pou\u017eit\u00edm Dako PT Link (Agilent, Santa Clara, CA, USA); rezy boli inkubovan\u00e9 v roztoku TRIS-EDTA (10 mM TRIS, 1 mM
\nEDTA pH 9) pri teplote 98 \u00b0C po\u010das 20 min\u00fat. Prepar\u00e1ty boli n\u00e1sledne inkubovan\u00e9 60 min\u00fat s my\u0161acou monoklon\u00e1lnou protil\u00e1tkou proti CD8 (ready to use, Agilent, Santa Clara, CA,
\nUSA), proti CD4 (ready to use, DAKO, Carpinteria, USA) a proti CD68 (ready to use, Agilent, Santa Clara, CA, USA). Po 3-n\u00e1sobnom prepl\u00e1chnut\u00ed v PBS, boli prepar\u00e1ty inkubovan\u00e9 30 min\u00fat s polym\u00e9rom Histofine proti my\u0161ac\u00edm prote\u00ednom (Nichirei Biosciences, Japonsko) a po opakovanom 3-n\u00e1sobnom prepl\u00e1chnut\u00ed v roztoku PBS farben\u00e9 5 min\u00fat diaminobenzid\u00ednom
\n(DAB+, DAKO, Carpinteria, USA). Prepar\u00e1ty boli n\u00e1sledne kr\u00e1tko dofarben\u00e9 hematoxyl\u00ednom, aby sa zv\u00fdraznili jadr\u00e1 buniek. Prepar\u00e1ty boli hodnoten\u00e9 vo svetelnom mikroskope. Miera
\ninfiltr\u00e1cie tkaniva z\u00e1palov\u00fdmi bunkami s pr\u00edslu\u0161n\u00fdm fenotypom bola hodnoten\u00e1 kvantitat\u00edvne v 3 n\u00e1hodn\u00fdch poliach s pou\u017eit\u00edm histomorfometrick\u00e9ho softv\u00e9ru ImageJ, v. 1,51 g(5) a vyjadren\u00e1 ako percento proti celkovej ploche. V\u00fdsledky boli vyhodnoten\u00e9 \u0161tatisticky pou\u017eit\u00edm \u0161tatistick\u00e9ho softv\u00e9ru Graph Pad Prism s pou\u017eit\u00edm one-way ANOVA testu s n\u00e1sledn\u00fdm Turkey post-testom, hodnoty p < 0,05 boli pova\u017eovan\u00e9 za signifikantn\u00e9.<\/p>\n

 <\/p>\n

V\u00fdsledky<\/strong>
\nV n\u00e1doroch hrub\u00e9ho \u010dreva aj v okolitom nepostihnutom tkanive pozorujeme pr\u00edtomnos\u0165 CD8+ cytotoxick\u00fdch T-lymfocytov, CD4+ pomocn\u00fdch T-lymfocytov (obr\u00e1zok 1) aj CD68+ histiocytov (obr\u00e1zok 2), s dominanciou CD68+ buniek. So st\u00fapaj\u00facim gradingom n\u00e1doru sme v na\u0161om s\u00fabore pozorovali signifikantn\u00fd pokles CD4+ (1,6 \u00b1 0,43 % v G1 verzus 0,33 \u00b1 0,08 % v G2, verzus
\n0,42 \u00b1 0,17 % v G3, G1\/G2 p < 0,001, G1\/G3 p < 0,05) aj pokles CD8+ cytotoxick\u00fdch T-lymfocytov (3,1 \u00b1 0,38 % v G1 verzus 1,7 \u00b1 0,3 % v G2 verzus 0,61 \u00b1 0,14 % v G3, G1\/G2 p < 0,05, G1\/ G3 p < 0,01). Pokles CD68+ histiocytov (5,3 \u00b1 0,46 % v G1 verzus 4,1 \u00b1 0,51 % v G2 verzus 3,44 \u00b1 0,67 % v G3, G1\/G2 p = 0,05) bol na hranici signifikantnosti (graf 1). Nepozorovali sme \u017eiadne zmeny v podiele jednotliv\u00fdch typov lymfocytov v okolitom tkanive nepostihnutom n\u00e1dorom (graf 2). Nepozorovali sme odli\u0161n\u00fd profil z\u00e1palov\u00fdch buniek v s\u00favislosti s mucin\u00f3znou diferenci\u00e1ciou n\u00e1doru, t\u00e1 dosahovala \u00farove\u0148 pribli\u017ene rovnak\u00fa ako n\u00e1dory so strednou diferenci\u00e1ciou\u00a0 (G2).<\/p>\n

 <\/p>\n

Diskusia<\/strong>
\nKolorekt\u00e1lny adenokarcin\u00f3m patr\u00ed medzi naj\u010dastej\u0161ie sa vyskytuj\u00face gastrointestin\u00e1lne malignity s vysokou mortalitou napriek dostupnej lie\u010dbe. Ukazuje sa, \u017ee samotn\u00fd staging zalo\u017een\u00fd na TNM klasifik\u00e1cii kolorekt\u00e1lneho karcin\u00f3mu nie je dostato\u010dne presn\u00fd z h\u013eadiska predikcie progn\u00f3zy pri v\u0161etk\u00fdch \u0161t\u00e1di\u00e1ch choroby(6). S\u00fa\u010dasn\u00fd v\u00fdskum vedie k h\u013eadaniu prognostick\u00fdch markerov, ktor\u00e9 by lep\u0161ie stratifikovali pacientov. Prospe\u0161n\u00e9 by mohlo by\u0165 aj hodnotenie pacientov zalo\u017een\u00e9 na imunologickom profile n\u00e1dorov\u00e9ho mikroprostredia(7).
\nPo\u010det vedeck\u00fdch d\u00f4kazov podporuj\u00facich v\u00fdznam imunitnej odpovede pri n\u00e1dorov\u00fdch chorob\u00e1ch neust\u00e1le rastie(3). S\u00fa\u010dasn\u00e9 terapeutick\u00e9 met\u00f3dy pou\u017e\u00edvan\u00e9 v lie\u010dbe kolorekt\u00e1lneho
\nkarcin\u00f3mu (cytotoxick\u00e1 chemoterapia, anti-EGFR protil\u00e1tky, anti-angiog\u00e9nne molekuly) \u010diasto\u010dne s\u00favisia s imunomoduluj\u00facimi mechanizmami a imunoterapia preuk\u00e1zala svoj potenci\u00e1l aj v pr\u00edpadoch, ke\u010f zlyh\u00e1va klasick\u00e1 lie\u010dba(8-10). Kolorekt\u00e1lny karcin\u00f3m je zn\u00e1my tvorbou vysokoimunog\u00e9nnych n\u00e1dorov\u00fdch neoantig\u00e9nov a je sprev\u00e1dzan\u00fd zv\u00fd\u0161enou infiltr\u00e1ciou tkaniva z\u00e1palov\u00fdmi bunkami, ktor\u00fa sme pozorovali aj v na\u0161ej \u0161t\u00fadii. Tento mechanizmus je mimoriadne zauj\u00edmav\u00fd najm\u00e4 v pr\u00edpade n\u00e1dorov s mikrosatelitovou instabilitou (MSI), kde vznikaj\u00fa presne definovan\u00e9 n\u00e1dorov\u00e9 neoantig\u00e9ny v d\u00f4sledku zn\u00e1mych molekul\u00e1rnych dr\u00e1h zasiahnut\u00fdch mut\u00e1ciou (tzv. frameshift peptidy)(11). Lymfocyty infiltruj\u00face tumor (TIL) a makrof\u00e1gy asociovan\u00e9 s n\u00e1dorom (TAM) s\u00fa lokalizovan\u00e9 v z\u00e1palovom infiltr\u00e1te okolo n\u00e1dorov\u00fdch ostrov\u010dekov a taktie\u017e v perin\u00e1dorovej. TAM patria medzi dominantn\u00e9 z\u00e1palov\u00e9 bunky v n\u00e1dorovej str\u00f3me. Spr\u00e1vaj\u00fa sa ako modul\u00e1tory mikroprostredia pomocou vylu\u010dovania cytok\u00ednov, chemok\u00ednov, rastov\u00fdch faktorov a angiog\u00e9nnych faktorov(12). To s\u00fahlas\u00ed aj s dominanciou CD68+ z\u00e1palov\u00fdch buniek v n\u00e1dorovom tkanive nami pozorovanou.<\/p>\n

\u00daloha TAM v n\u00e1dore je dvojit\u00e1. TAM m\u00f4\u017eeme deli\u0165 do dvoch podskup\u00edn: M1 makrof\u00e1gy zabezpe\u010duj\u00fa protin\u00e1dorov\u00fa odpove\u010f a cytotoxicitu a M2 makrof\u00e1gy, ktor\u00e9, naopak, potla\u010den\u00edm protin\u00e1dorovej imunitnej odpovede podporuj\u00fa n\u00e1dorov\u00fa progresiu(13,14). Z TIL maj\u00fa k\u013e\u00fa\u010dov\u00fa \u00falohu cytotoxick\u00e9 T-lymfocyty CD8+, ktor\u00e9 m\u00f4\u017eu rozpozna\u0165 n\u00e1dorov\u00e9 antig\u00e9ny prezentovan\u00e9 APC bunkami. Cytotoxick\u00e9 T-lymfocyty sa n\u00e1sledne aktivuj\u00fa pomocou kostimul\u00e1torov\u00fdch molek\u00fal a synetizuj\u00fa a vylu\u010duj\u00fa cytotoxick\u00e9 prote\u00edny podie\u013eaj\u00face sa na priamej de\u0161trukcii n\u00e1dorov\u00fdch buniek. Vysok\u00e1 hustota CD8+ lymfocytov v n\u00e1dorovom tkanive je spojen\u00e1 s lep\u0161ou progn\u00f3zou choroby(12). Je zauj\u00edmav\u00e9, \u017ee v na\u0161om s\u00fabore sme pozorovali pokles CD8+ lymfocytov aj ostatn\u00fdch pozorovan\u00fdch z\u00e1palov\u00fdch buniek v z\u00e1vislosti od rast\u00faceho gradingu a st\u00fapaj\u00facej agresivity tumoru. M\u00f4\u017ee to podporova\u0165 predstavu o imunosupres\u00edvnom p\u00f4soben\u00ed n\u00e1dorov\u00e9ho mikroprostredia(4), ktor\u00e9 m\u00f4\u017ee by\u0165 d\u00f4le\u017eit\u00fdm faktorom progresie choroby aj pri vzniku vzdialen\u00fdch metast\u00e1z(15). Viacer\u00e9 \u0161t\u00fadie preuk\u00e1zali, \u017ee imunitn\u00e1 odpove\u010f koreluje s lep\u0161\u00edm pre\u017e\u00edvan\u00edm pacientov s kolorekt\u00e1lnym karcin\u00f3mom(16,17). Predlo\u017een\u00e1 \u0161t\u00fadia nazna\u010duje, \u017ee v s\u00favislosti so zvy\u0161uj\u00facim sa gradingom n\u00e1doru doch\u00e1dza k poklesu intenzity protin\u00e1dorovej imunitnej odpovede. Tento pokles m\u00f4\u017ee by\u0165 n\u00e1sledkom, ale aj pr\u00ed\u010dinou progresie tumoru. Pr\u00e1ve ovplyvnenie protin\u00e1dorovej imunitnej odpovede m\u00f4\u017ee predstavova\u0165 potenci\u00e1lne
\nzauj\u00edmav\u00fd terapeutick\u00fd pr\u00edstup.<\/p>\n

 <\/p>\n

Po\u010fakovanie:<\/strong> \u0160t\u00fadia bola realizovan\u00e1 s podporou projektuAPVV-14-0318 \u201eAnal\u00fdza mikroRNA a charakteriz\u00e1cia expresie vybran\u00fdch prote\u00ednov v cirkadi\u00e1nnom kontexte ako prognostick\u00fd
\nbiomarker pre kolorekt\u00e1lny karcin\u00f3m\u201c. \u0160t\u00fadia bola parci\u00e1lne realizovan\u00e1 ako s\u00fa\u010das\u0165 pr\u00e1ce v\u00fdskumn\u00e9ho centra vybudovan\u00e9ho v\u010faka podpore v r\u00e1mci OP V\u00fdskum a v\u00fdvoj preprojekt: \u201eDobudovanie multidisciplin\u00e1rneho centra pre biomedic\u00ednsky v\u00fdskum \u2013 BIOMEDIRES\u201c, ITMS 26210120041, spolufinancovan\u00fd zo zdrojov Eur\u00f3pskeho fondu region\u00e1lneho rozvoja.<\/p>\n

 <\/p>\n

 <\/p>\n

LITERAT\u00daRA<\/strong>
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\n3. de la Cruz-Merino L, Henao Carrasco F, Vicente Baz D, et al. Immune microenvironment in colorectal cancer: a new hallmark to change old paradigms. Clin Dev Immunol 2011; 2011: 174149.
\n4. Naidoo J, Page DB, Wolchok JD. Immune modulation for cancer therapy. Br J Cancer 2014; 111(12): 2214-9.
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\n6. Liu Q, Luo D, Cai S, et al. P-TNM staging system for colon cancer: combination of P-stage and AJCC TNM staging system for improving prognostic prediction and clinical management. Cancer Manag Res 2018; 10: 2303\u20112314.
\n7. Nearchou A, Pentheroudakis G. The significance of tumor-associated immune response in molecular taxonomy, prognosis and therapy of colorectal cancer patients. Ann Transl Med 2016; 4(14): 271.
\n8. Pernot S, Terme M, Voron T, et al. Colorectal cancer and immunity: what we know and perspectives. World J Gastroenterol 2014; 20(14): 3738-50.
\n9. Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter- inhibitory checkpoints. Cancer Discov 2015; 5(1): 43-51.
\n10. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28(19): 3167-75.
\n11. Kloor M, von Knebel Doeberitz M. The Immune Biology of Microsatellite-Unstable Cancer. Trends in Cancer 2016; 2(3): 121-133.
\n12. Colangelo T, Polcaro G, Muccillo L, et al. Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochim Biophys Acta Rev Cancer 2017; 1867(1): 1-18.
\n13. Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017.
\n14. Grizzi F, Basso G, Borroni EM, et al. Evolving notions on immune response in colorectal cancer and their implications for biomarker development. Inflamm Res 2018; 67(5): 375-389.
\n15. Donahue T, Lee CY, Sanghvi A, et al. Immunosuppression is an independent prognostic factor associated with aggressive tumor behavior in cutaneous melanoma. J Am Acad Dermatol 2015; 73(3): 461-6.
\n16. Ogino S, Nosho K, Irahara N, et al. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res 2009; 15(20): 6412-20.
\n17. Sinicrope FA, Rego RL, Ansell SM, et al. Intraepithelial effector (CD3+)\/ regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009; 137(4): 1270-9.<\/p>\n","protected":false},"excerpt":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod Zhubn\u00e9 n\u00e1dory hrub\u00e9ho \u010dreva patria medzi najpo\u010detnej\u0161ie mal\u00edgne ochorenia vo vyspel\u00fdch \u0161t\u00e1toch sveta. Slovensk\u00e1 republika sa nach\u00e1dza na jednom z popredn\u00fdch miest v celosvetovom rebr\u00ed\u010dku, v Eur\u00f3pe m\u00e1<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[297],"tags":[1247,1248,1249],"class_list":["post-1784","post","type-post","status-publish","format-standard","hentry","category-pathology","tag-colorectal-carcinoma","tag-immune-response","tag-tumor-microenvironment","typ_clanku-original-work"],"acf":{"abstrakt":"

Colorectal cancer is one of the most common oncological diseases with high mortality. The immune system and the tumour-related immune response mediated by tumour-infiltrating lymphocytes play an important role in tumour behaviour and progression. The presented study aimed to assess the activation of the immune system in colorectal tumours with a focus on the inflammatory cell phenotype. The inflammatory cell infiltration was evaluated in 23 colorectal cancer samples. The presence and density of infiltration of cytotoxic (CD8+) and helper (CD4+) T-lymphocytes and histiocytes (CD68 +) were analyzed inside tumours as well as in the surrounding non-neoplastic tissue. The samples were processed to microarray and immunohistochemically stained. The positivity was evaluated quantitatively by computer image analysis. The present study showed that the intensity of the antitumour immune response decreases in connection with increasing tumour grading. The decrease might be due to tumour progression. But it also might be the cause of this decrease. The influencing of the anti-tumour immune response represents a very interesting potential therapeutic approach.<\/p>\n

Keywords:<\/strong> colorectal carcinoma, immune response, tumor microenvironment<\/p>\n","casopis":[{"ID":1883,"post_author":"7","post_date":"2019-10-28 13:35:57","post_date_gmt":"2019-10-28 12:35:57","post_content":"