Composition and prognostic significance of T helper lymphocytes in lung cancer

Lung cancer is the most fatal cancer worldwide with non-small cell lung cancer and its subtypes adenocarcinoma and squamous cell carcinoma accounting for approximately 80% of all lung cancer cases. In lung cancer treatment immunotherapies, such as PD-L1 checkpoint inhibitors, are widely in use along...

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Main Author: Kivelä, Essi
Other Authors: Faculty of Sciences, Matemaattis-luonnontieteellinen tiedekunta, Department of Biological and Environmental Science, Bio- ja ympäristötieteiden laitos, University of Jyväskylä, Jyväskylän yliopisto
Format: Master's thesis
Language:eng
Published: 2024
Subjects:
Online Access: https://jyx.jyu.fi/handle/123456789/95519
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author Kivelä, Essi
author2 Faculty of Sciences Matemaattis-luonnontieteellinen tiedekunta Department of Biological and Environmental Science Bio- ja ympäristötieteiden laitos University of Jyväskylä Jyväskylän yliopisto
author_facet Kivelä, Essi Faculty of Sciences Matemaattis-luonnontieteellinen tiedekunta Department of Biological and Environmental Science Bio- ja ympäristötieteiden laitos University of Jyväskylä Jyväskylän yliopisto Kivelä, Essi Faculty of Sciences Matemaattis-luonnontieteellinen tiedekunta Department of Biological and Environmental Science Bio- ja ympäristötieteiden laitos University of Jyväskylä Jyväskylän yliopisto
author_sort Kivelä, Essi
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description Lung cancer is the most fatal cancer worldwide with non-small cell lung cancer and its subtypes adenocarcinoma and squamous cell carcinoma accounting for approximately 80% of all lung cancer cases. In lung cancer treatment immunotherapies, such as PD-L1 checkpoint inhibitors, are widely in use alongside the conventional cancer treatments surgery, radiation, and chemotherapy to improve treatment outcome and survival rate. Immune cell density and composition are heterogenous between tumors and different tumor sites, and research could help better understand the interactions between host tissue and tumor to reveal possible new targets for immunotherapy, as well as new prognostic biomarkers. Multiplex immunohistochemistry enables the use of several monoclonal antibodies for the same tissue section so that many different types of immune cells and their relations to each other to be investigated for effective biomarker research. In the thesis study different subtypes of T lymphocytes, innate lymphoid cells (ILCs), macrophages, and natural killer (NK) cells were stained using specific monoclonal antibodies to calculate respective cell densities within the central tumor and invasive margin of lung cancer tumors. CD8+ and CD4+ T lymphocytes, ILCs, NK cells and macrophages were phenotyped in QuPath bioimage analysis software, while regulatory T lymphocytes, T helper lymphocyte subtypes Th1, Th2, and Th17, and ILC subtypes ILC1, ILC2, and ILC3 were phenotyped by intensity thresholds. Density calculations for each cell type within the tumor center and invasive margin were made. Together with extensive patient data the effect of Th1, Th2, and Th17 on long-term survival was assessed. Th17 was found to have a statistically significant impact on cancer-specific survival three years post operation in the tumor center, and five years post operation both in the tumor center and invasive margin. The findings are, however, contradictory to most results in literature, and more research needs to be made to specify why such results were obtained. Maailmanlaajuisesti keuhkosyöpä on kuolettavin kaikista syövistä. Ei-pienisoluinen keuhkosyöpä ja sen alatyypit adeno- ja levyepiteelikarsinooma kattavat noin 80 % kaikista keuhkosyöpätapauksista. Immunoterapiaa, kuten PD-L1 inhibiittoreita, käytetään jo keuhkosyövän hoidossa yhdessä perinteisten hoitomuotojen, kuten leikkauksen, säteilyhoidon ja kemoterapian, kanssa, jolloin hoito on tehokkaampaa ja suhteellinen elossaololuku nousee. Immuunisolujen sijainti ja määrä voi vaihdella suuresti kasvaimen eri alueiden ja potilaiden välillä. Näiden eroavaisuuksien ja keskinäisen vuorovaikutuksen ymmärtäminen auttaa löytämään ja tunnistamaan uusia immunoterapiakohteita sekä prognostisia biomarkkereita. Useiden eri immuunisolujen ja niiden keskinäisten suhteiden tutkiminen on mahdollista syklisen multiplex immunohistokemiallisen värjäysmenetelmän avulla. Syklinen värjäysmenetelmä mahdollistaa jokaisen solun tunnistamisen ja luokittelun usean markkerin avulla samanaikaisesti. Lisäksi solujen välisiä spatiaalisia suhteita ja solutiheyksiä voidaan mitata ja laskea tietokoneavusteisesti. Tutkimuksessa tutkittiin T lymfosyyttejä, luonnollisia lymfosyyttejä (engl. innate lymphoid cell, ILC), makrofageja sekä luontaisia tappajasoluja (engl. natural killer cells, NK cells), jotka värjättiin spesifeillä monoklonaalisilla vasta-aineilla, ja niiden tiheydet keuhkokasvaimen keskellä ja invaasiorintamalla laskettiin. CD8+ ja CD4+ lymfosyytit, ILC ja NK solut sekä makrofagit tunnistettiin QuPath kuva-analyysiohjelmistolla. Solut luokiteltiin alatyyppeihin (säätelevät T lymfosyytit, T-auttajasolujen alatyypit Th1, Th2 ja Th17, sekä ILC1, ILC2 ja ILC3 solut) intensiteettiraja-arvojen perusteella. Eri T lymfosyyttityyppien, ILC solujen, makrofagien, ja NK solujen solutiheydet kasvaimen keskustassa ja invaasiorintamassa laskettiin. Th1, Th2 ja Th17 solujen vaikutusta potilaiden pitkäaikaiseen selviytymiseen tutkittiin. Tilastollisesti merkittävä vaikutus syöpäspesifiin selviytymiseen kolme vuotta leikkauksen jälkeen saatiin Th17 solujen runsaasta esiintymisestä kasvaimen keskustassa, ja viisi vuotta leikkauksen jälkeen sekä kasvaimen keskustassa että invaasiorintamalla. Tulokset ovat ristiriidassa useimpien julkaisujen kanssa, joten lisää tutkimusta tarvitaan tulosten selittämiseksi.
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spellingShingle Kivelä, Essi Composition and prognostic significance of T helper lymphocytes in lung cancer Multiplex-immunohistochemistry T-helper lymphocytes tissue microarray Cell and molecular biology Solu- ja molekyylibiologia 4013 syöpätaudit keuhkosyöpä immunologia lymfosyytit immunohistokemia immuunijärjestelmä cancerous diseases pulmonary cancer immunology lymphocytes immunohistochemistry immune system
title Composition and prognostic significance of T helper lymphocytes in lung cancer
title_full Composition and prognostic significance of T helper lymphocytes in lung cancer
title_fullStr Composition and prognostic significance of T helper lymphocytes in lung cancer Composition and prognostic significance of T helper lymphocytes in lung cancer
title_full_unstemmed Composition and prognostic significance of T helper lymphocytes in lung cancer Composition and prognostic significance of T helper lymphocytes in lung cancer
title_short Composition and prognostic significance of T helper lymphocytes in lung cancer
title_sort composition and prognostic significance of t helper lymphocytes in lung cancer
title_txtP Composition and prognostic significance of T helper lymphocytes in lung cancer
topic Multiplex-immunohistochemistry T-helper lymphocytes tissue microarray Cell and molecular biology Solu- ja molekyylibiologia 4013 syöpätaudit keuhkosyöpä immunologia lymfosyytit immunohistokemia immuunijärjestelmä cancerous diseases pulmonary cancer immunology lymphocytes immunohistochemistry immune system
topic_facet 4013 Cell and molecular biology Multiplex-immunohistochemistry Solu- ja molekyylibiologia T-helper lymphocytes cancerous diseases immune system immunohistochemistry immunohistokemia immunologia immunology immuunijärjestelmä keuhkosyöpä lymfosyytit lymphocytes pulmonary cancer syöpätaudit tissue microarray
url https://jyx.jyu.fi/handle/123456789/95519 http://www.urn.fi/URN:NBN:fi:jyu-202406054280
work_keys_str_mv AT kiveläessi compositionandprognosticsignificanceofthelperlymphocytesinlungcancer