Tumor Immunology of Ovarian Cancer
Het immuunsysteem als bondgenoot in de strijd tegen kanker
In dit thesisonderzoek werd de specifieke rol van het immuunsysteem in eierstokkanker nagegaan.
Een sluipende en succesvolle doder
Eierstokkanker is een agressieve kanker die de belangrijkste oorzaak vormt van gynaecologische sterfte bij vrouwen. Eierstokkanker geeft weinig of geen klachten. Daardoor kan hij zich volledig verspreiden in de gehele buikholte voordat er nog maar de minste ongemakken ontstaan. Als er toch symptomen zouden zijn, zijn deze vaak niet-specifiek en niet ernstig genoeg om een dokter te contacteren: een opgeblazen gevoel, vage buikpijn en vermoeidheid. Wanneer eierstokkanker toch vastgesteld wordt, bevindt die zich dan ook vaak in een vergevorderd stadium. Momenteel bestaat de huidige behandeling uit een uitgebreide chirurgische ingreep waarbij alle kankergezwellen worden weggenomen. Dit wordt aangevuld met chemotherapie. De ganse behandeling duurt een zestal maanden. Helaas hervallen veel patiënten en vaak reageert de teruggekeerde tumor niet meer voldoende op chemotherapie. Minder dan 20% van de patiënten is nog in leven, vijf jaar na de diagnose. Er is dus een hoge nood aan nieuwe wapens om deze ziekte beter te kunnen gaan bestrijden. Daarin zien mijn collega’s en ikzelf het immuunsysteem als onze nieuwe bondgenoot.
Soldaten tegen kanker
Het immuunsysteem functioneert als een goed geoliede machine dat een leger aan witte bloedcellen gebruikt om het menselijke lichaam te verdedigen tegen allerlei indringers: bacteriën, virussen, maar ook kankercellen. Cellen van het immuunsysteem zijn in staat om kankercellen te herkennen en te vernietigen. Op deze manier beschermt het immuunsysteem ons, net zoals dat het geval is wanneer we een verkoudheid hebben. Immunotherapieën, die dit immuunsysteem manipuleren om zo kanker te kunnen bestrijden, kennen de laatste jaren een enorme opmars. Voor sommige kankers, zoals bijvoorbeeld huidkanker, boeken deze immunotherapieën grote successen. Daarom worden deze succesvolle – maar ook dure – immunotherapieën geopperd als behandeling voor bijna alle kankers in klinische studies. Echter, voor heel wat soorten kanker, waaronder eierstokkanker, blijft het succesverhaal afwezig. Een mogelijke verklaring voor dit falen ligt vermoedelijk in het feit dat het gedrag van het immuunsysteem (dat men probeert te veranderen met immunotherapie) anders en specifiek is voor elke kanker. En met dat gegeven wordt op dit moment niet echt rekening gehouden in de lancering van immunotherapie.
Op zoek naar een strategisch aanvalsplan
Welke immuuncellen zijn dan belangrijk bij eierstokkanker? Hoe werken ze? Hoe en met welke wapens kunnen we ze beïnvloeden en zo de mensen langer laten leven? Omdat de mens moeilijk als proefpersoon kan gebruikt worden, wordt het onderzoek uitgevoerd op muizen met eierstokkanker. Deze muis ontwikkelt eierstokkanker net zoals een mens. In een allereerste experiment gingen we na of een speciaal type immuun cel, meer bepaald de “myeloid afgeleide onderdrukkende cellen (myeloid derived suppressor cells)”, kortweg MDSC, een rol speelt in eierstokkanker. Deze cel is nog niet zo lang gekend bij onderzoekers. MDSC zijn in vele opzichten speciale cellen. Ze zijn onvolwassen en jong van aspect (immatuur), waardoor ze - in tegenstelling tot hun volwassen equivalenten - immunosuppressieve capaciteiten bezitten. Dit betekent bijvoorbeeld dat ze andere (volwassen) immuun cellen, bijvoorbeeld een T-cel, kunnen tegenhouden wanneer deze een kankercel zouden willen aanvallen en elimineren. Ze gaan er eigenlijk voor zorgen dat de tumor meer kansen krijgt om zich te ontwikkelen. In deze thesis konden wij vaststellen dat het aantal MDSC steeg naarmate eierstokkanker zich verder ontwikkelde (meer uitzaaiingen). Onze interesse was gewekt. We gingen een stapje verder en konden aantonen dat in een kweekschaaltje die bewuste MDSC effectief in staat waren de goede T-cellen volledig te verlammen. De T-cellen konden niet meer delen en meer nog, ze moesten in aantal inboeten en werden vervangen door regulerende T-cellen, waarvan ook geweten is dat ze de groei van de kanker bevorderen. Om zeker te zijn van de belangrijke rol van MDSC in eierstokkanker gebruikte we ook nog een genetisch gemanipuleerde muis die geen MDSC heeft. Hier zagen we duidelijk dat muizen mét MDSC veel sneller ziek werden van hun kanker dan de muizen zonder MDSC.
Voldoende bewijs dus voor ons dat MDSC een belangrijke invloed uitoefent bij de ontwikkeling van eierstokkanker, maar hoe kunnen we deze nu tegen houden? Dit onderzoek is nog in volle ontwikkeling maar we hebben reeds de effecten van de meest gebruikte chemotherapieën bij eierstokkanker bekeken. Carboplatinum-Paclitaxel (onze nummer één keuze van chemotherapie bij eierstokkanker) kwam als winnaar uit de bus met een positief effect op het totale immuunsysteem, echter, zonder duidelijke vermindering in MDSC.
Deze thesis heeft belangrijke informatie toegevoegd aan de immunologische puzzel. MDSC hebben zeker een sleutelrol. Maar ze aanvallen is nog een andere zaak. We mogen ook niet vergeten dat deze MDSC niet alleen zijn in ons lichaam en dat therapie gericht tegen hen ongetwijfeld effecten zal hebben op andere cellen. Om immunotherapieën zinvol te kunnen gebruiken als anti-kanker middelen hebben we duidelijk nog meer inzichten nodig. Meer dan waarschijnlijk ligt het antwoord voor een succesvolle behandeling in een combinatie van verschillende soorten therapieën, op het juiste moment, in de juiste volgorde. Daarom dat mijn collega’s en ikzelf dagelijks onderzoek blijven doen om dit mysterie verder te ontrafelen, zodat we patiënten uiteindelijk een succesvolle nieuwe behandeling kunnen geven.
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