Sinergistički efekat blokade IL-33/ST2 i PDL/PD-1 osovina na progresiju mišjeg karcinoma dojke
Synergistical effect of IL-33/ST2 and PDL/PD-1 blockage in a mammary carcinoma
Докторанд
Jovanović, MarinaМентор
Jovanović, IvanЧланови комисије
Arsenijević, NebojšaRadosavljević, Gordana
Jovanović, Milan
Метаподаци
Приказ свих података о дисертацијиСажетак
Iako je dobro poznato da pojedinačna blokada bilo PDL/PD-1 bilo IL-33/ST2 osovine
doprinosi efikasnijem anti-tumorskom odgovoru, simulantana blokada ovih osovina
nije još uvek izučena. Indukovali smo karcinom dojke (4T1) ili karcinom kolona
(ST26) BALB/c ili BALB/c ST2 nokaut miševima, a potom su dobijali anti PD-1 ili
anti IL-33 antitelo Simultana blokada IL33/ST2 i PDL/PD1 je odložila pojavu
palpabilnog tumora i usporila rast tumora. Naši rezultati takođe ukazuju pojačanu
citotoksičnost NK ćelija prema 4T1 tumorskim ćelijama kod ST2 nokaut miševa koji su
tretirani anti-PD-1 anitelom. Kod ST2 nokaut miševa koji su tretirani anti-PD-1
anitelom je takođe bila povećana ekspresija miRNA-150 i miRNA-155, povećanje
ekspresije NFκB i STAT3, povećana ekspresija aktivacionih markera i smanjena
ekspresija imunsupresivnih markera kod NK, NKT, T limoficita, u slezini i u
primarnom tumoru. Takođe, NK ćelije izolovane iz BALB/cST2 nokaut miševa koji su
tretirani anti-PD-1 anitelom, imaj...u veči stepen proliferacije i manji stepen apoptoze
u primarnom tumoru. Akumulacija imusupresivnih ćelijskih populacija mijeloidnih
supresorskih ćelija il iT regulatornih limfocita, je kod ST2 nokaut miševa koji su
tretirani anti-PD-1 anitelom bila značajno manja i u slezini i uz priamrnom tumoru.
Ovi rezultati pokazuj uda simultana blokada IL-33/ST2 i PDL/PD-1 osovina mnogo
efikasnije usporava progresiju tumora u odnosu na pojedinačnu blokadu, otvarajući
nove mogućnosti za terapijski pristum lečenju karcinoma.
Although separate blockage of either IL-33/ST2 or PDL/PD-1 axes has been shown to be
beneficial in many tumors, co-blockage of IL33/ST2 and PDL/PD-1 hasn’t been studied yet.
4T1 breast cancer and CT26 colon cancer were inducted in BALB/C wild type (WT) and
BALB/C ST2 knockout mice, after which mice underwent anti PD1 and anti IL-33 treatment.
Co-blockage of IL33/ST2 and PDL/PD1 delayed tumor appearance and slowed tumor growth.
Enhanced NK cell cytotoxicity against 4T1 tumor cells in ST2 knockout anti-PD1 treated mice
was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and
STAT3, increased expression of activation markers and decreased expression of
immunosuppressive markers in splenic and primary tumor derived NK cells. NK cells from ST2
knockout anti-PD1 treated mice tend to proliferate more and are less prone to apoptosis.
Accumulation of immunosuppressive myeloid derived suppressor cells and regulatory T cells
was significantly impaired in ...spleen and primary tumor of ST2 knockout anti-PD1 treated mice.
Co-blockage of IL-33/ST2 and PDL/PD-1 axes impedes tumor progression more efficiently than
single blockage of either axes, thus offering potential new approach to immunotherapy of
tumors.