HAL Id: tel-01320989https://tel.archives-ouvertes.fr/tel-01320989

Submitted on 24 May 2016

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La transition épithélio-mésenchymateuse régulel’expression de PD-L1 dans le cancer du poumon, non à

petites cellules : un role pour IKK �Afag Asgarova

To cite this version:Afag Asgarova. La transition épithélio-mésenchymateuse régule l’expression de PD-L1 dans le cancerdu poumon, non à petites cellules : un role pour IKK �. Médecine humaine et pathologie. Universitéde Franche-Comté, 2015. Français. �NNT : 2015BESA3007�. �tel-01320989�

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La transition epithelio-m!senchymateuse r!gule l"expression de PD-L1 dans le cancer du poumon non #

petites cellules: un r$le pour IKKε.

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UNIVERSITE DE FRANCHE-COMTE

UFR SCIENCES MEDICALES ET PHARMACEUTIQUES DE

BESANCON

Année Universitaire 2014-2015

THESE

Pour l’obtention du Diplôme de Doctorat de l’Université de Franche-Comté Spécialité : Sciences de la Vie et de la Santé

Présentée et soutenue publiquement par

Afag ASGAROVA

Le 2 octobre 2015

La transition épithelio-mésenchymateuse régule

l’expression de PD-L1 dans le cancer du poumon non à

petites cellules: un rôle pour IKKε.

Sous la direction du Professeur Christophe BORG

Membres du Jury :

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('GG*G'.!.*O%..>;)!*;'!FAI!T0'&>G)>!N1G'&!')!>G@9!\bbbU@!L'!4>..>P'!+Y*;!=)>)!4&1K>+,=.%2!TG%=!X!

GY'B4&'..%1;! +'! G>! AK(>+,=&%;'U9! X! *;! =)>)! 4&1KC%P&>)1%&'! T><'(! 'B4&'..%1;! +'! (>+,=&%;'.!

.4=(%2%V*'.!+=<'G144>;)!+'.!%;)'&>()%1;.!4G*.!2>%OG'.!')!4G*.!4'&C%..%<'.!X!G>!C1O%G%)=U!&';+!!

GY%;<>.%1;! )*C1&>G'! ')! G'.! C=)>.)>.'.! 41..%OG'.! T3><>GG>&1! >;+! 3,&%.)121&%9! "ffQU@! L>!

<%C';)%;'!'.)!+'<';*'!*;!C>&V*'*&!4>&!'B('GG';('!+'.!4,=;1C-;'.!+'!FAI!+>;.!4&'.V*'!

)1*.!G'.!4&1('..*.!4,S.%1G1P%V*'.!1*!4>),1G1P%V*'.!TD>S!>;+!p*]9!\bbRU@!L>!<%C';)%;'!'.)!*;!

C'CO&'! +'! G>! 2>C%GG'! +'.! 2%G>C';).! %;)'&C=+%>%&'.! V*%! (1;.)%)*'! G'! (S)1.V*'G'))'! ><'(! G'.!

C%(&1)*O*G'.!')!G'.!C%(&12%G>C';).!+Y>()%;'@!I>%.!G>!<%C';)%;'!'.)!*;'!.)&*()*&'!+S;>C%V*'9!

';! +%22=&';('! +'! G>! 4G*4>&)! +'.! 2%G>C';).! ><'(! +'.! .)&*()*&'.! .)>OG'.@! LY%;+*()%1;! +'! G>!

<%C';)%;'!'.)!(1&&=G='!X!+'.!4&14&%=)=.!C%P&>)1%&'.!')!%;<>.%<'!+'!;1CO&'*B!(>;('&.!TN%;P,!

')! >G@9! "ff#UTg1&.(,%;P! ')! >G@9! "ffRU!w! >%;.%! G>! 4'&)'! +Y'B4&'..%1;! +'! G>! <%C';)%;'! &=+*%)! G>!

(&1%..>;('!)*C1&>G'Tp,>;P!')!>G@9!"ffbUTt*!')!>G@9!"ffb>U@!LY'B4&'..%1;!+'! G>!<%C';)%;'!'.)!

(1&&=G='!X!*;!C>*<>%.!4&1;1.)%V*'!+>;.!+'.!O%14.%'.!+'.!(>&(%;1C'.!+*!.'%;9!+*!41*C1;9!

+'.! 1<>%&'9! +'! G>! ),S&1�+'9! ! +*! &'%;9! +'! G>! 4&1.)>)'! ')! +'! G>! 4'>*! TL'>+'&! ')! >G@9!

\bedUT$1C>P>G>!')!>G@9!\bbfUTg1]]%;1.!')!>G@9!"ffdU@!

Le phénotype CSCs

L'.!3N3.!T('GG*G'.!.1*(,'.!+*!(>;('&U!.1;)!+'.!('GG*G'.!4&=.';)'.!+>;.!+'!;1CO&'*.'.!

)*C'*&.!(>4>OG'.!+W>*)1K&';1*<'GG'C';)!41*&!%;%)%'&!G>!)*C1&%P=;-.'@!L'.!3N3.!.1;)!G%='.!X!

G>! 21&C>)%1;! +'! C=)>.)>.'.9! GW%;<>.%1;! ')! G>! &=.%.)>;('! >*B! )&>%)'C';).@! 3$QQ9! 3$\##! ')!

3$\cc!.1;)!+'.!C>&V*'*&.!+'!3N3.@!HG!S!>!*;'!&'G>)%1;!(1C4G'B'!';)&'!G>!FAI9!G'!4,=;1)S4'!

3N3.! ')! G'! (1C41&)'C';)! >P&'..%2! +'.! ('GG*G'.! (>;(=&'*.'.@! LW%;+*()%1;! +'! G>! FAI! 4>&!

+%22=&';).! 2>()'*&.! >O1*)%)! X! GW';&%(,%..'C';)! 4>&! G'.! 3N3.! >..1(%=! X! GW>44>&%)%1;! +'!

! Q"!

C=)>.)>.'.@!8&�('!X! GY>()%<>)%1;!+'!G>!<1%'!+'!.%P;>G%.>)%1;!7JNhIJ0g9!*;'!G%P;='!('GG*G>%&'!

=4%),=G%>G'! C>CC>%&'! ;1;! )*C1&%P-;'! T3$QQG1k! ')! 3$"Q,%P,U! 4'*)! =<1G*'&! <'&.! *;!

4,=;1)S4'! .1*(,'! T3$QQ,%P,! ')! 3$"QG1kU! +'! )S4'!C=.';(,SC>)'*B! V*%! .Y1O.'&<'! 4>&! G>!

4'&)'!+'!GYAK(>+,=&%;'!')!GW'B4&'..%1;!+'!G>!E%C';)%;'@!!J%;.%9!G>!4'&)'!+'!A!K(>+,=&%;'!>O1*)%)!

X! G>! FAI! ')! %;+*%)! ! *;'! >*PC';)>)%1;! +*! ;1CO&'! +'! ('GG*G'.! 3$QQ,%P,h3$"QG1k!

T8%;;'O>*P,!')!>G@9!"f\QU@!

)

E2)=(-)5K>(-),()873)

6;! 1O.'&<'! )&1%.! +%22=&';).! )S4'.! +'! FAI!+>;.! G'.! 4&1('..*.! 4,S.%1G1P%V*'.! ')!

4>),1G1P%V*'.@!

TEM physiologique

! L>! FAI! 4,S.%1G1P%V*'! .Y1O.'&<'! G1&.! +'! GY'CO&S1P';-.'! ')! G'! 4&1('..*.! +'!

(%(>)&%.>)%1;@!

TEM de type 1 (Embryogenèse)

$-.! G'! .)>+'! +'! 4&=K%C4G>;)>)%1;9! GY>44>&%)%1;! +'.! ('GG*G'.! =4%),=G%>G'.! ')! G'*&.!

(1;<'&.%1;.!';!('GG*G'.!C=.';(,SC>)'*.'.!'.)!1O.'&<='!(,'l! GY,1CC'@!L'!C=.1+'&C'!'.)!

*;!C=.';(,SC'!4&%C>%&'!!,D)4*5#+)L'(-(+%&K'*M)N)L'(-AM.)'#4#(D)(5)L(+%&K'*M.)#+OD-#A+2)

%..*! +'! GY>()%<>)%1;! +Y*;! 4&1P&>CC'! FAI! +>;.! G'.! ('GG*G'.! +'! GY=4%),=G%*C! =4%OG>.)%!"#$%

!"#$%&'()*+,#-./*%01*9!!"#!$%&'$%&($''#'$%&)*%$+(,-).'$%&+$&/*012$+!&3.%&/#&)*%"/$0)$4&

L'! +=<'G144'C';)! 'CO&S1;;>%&'9! GY1&P>;%.>)%1;! )&%+%C';.%1;;'GG'! +'! ;1CO&'*B! 1&P>;'.!

;=('..%)';)! )&-.! )Z)! G>! C%P&>)%1;! (11&+1;;='! +'! P&1*4'.! +'! ('GG*G'.! V*%! &=41;+';)! X! G>!

.)%C*G>)%1;!+'!.%P;>*B!(,%C%V*'.!'B)&>('GG*G>%&'.@!J*!(1*&.!+'! GY'CO&S1P';-.'9! G>!FAI!'.)!

%C4G%V*='!+>;.! G>!P>.)&*G>)%1;9! G>! 21&C>)%1;!+'! G>!(&u)'!;'*&>G'9!+'.!<>G<'.!(>&+%>V*'.!')(@!

TI'*G'C>;.! >;+! 5&1;;'&K_&>.'&9! "ffQUT8'&.,';P1&;! ')! >G@9! "ffQUTF,%'&S! >;+! NG''C>;9!

"ffcU@!3'!)S4'!+'!FAI!.'!2>%)!.1*.!G'!(1;)&ZG'!+'!.%P;>*B!G1(>*B!')!>O1*)%)!X!+'.!4,=;1)S4'.!

C=.';(,SC>)'*B!)&>;.%)1%&'.!')!&=<'&.%OG'.!+'.)%;=.!X!P=;=&'&!+'.!=4%),=G%*C.!.'(1;+>%&'.@!

L'!(>&>()-&'!&=<'&.%OG'!+'!G>!FAI!4>&!G'.!4&1('..*.!+'!)&>;.%)%1;.!C=.';(,SC1K=4%),=G%>G'.!

! Q#!

TIAFU!'.)!4&1O>OG'C';)!>44>&*!4G*.!)>&+!>*!(1*&.!+'!GY=<1G*)%1;@!L>!FAI!+'!)S4'!\!4'&C')!

=P>G'C';)!+'.!=)>4'.!+'!C1&4,1P';-.'!41*<>;)!%;)'&<';%&!+>;.!GY,1C=1.)>.%'!(,'l!GY>+*G)'!

TPG>;+'!C>CC>%&'9!*)=&*.9!;=1K!>;P%1P';-.'@@@U!T$'C%&!')!>G@9!"ffQU!

TEM de type 2 (Cicatrisation)

L>!FAI!+'!)S4'!"!'.)!>..1(%='!>*B!4,=;1C-;'.!+'!(%(>)&%.>)%1;!')!+'!&=P=;=&>)%1;!

)%..*G>%&'! >%;.%! V*Y>*B! 4>),1G1P%'.! 2%O&1)%V*'.@! 3'))'! FAI! '.)! %;%)%='! 4>&! +'.! .%P;>*B!

C1G=(*G>%&'.! 4&1K%;2G>CC>)1%&'.! .=(&=)=.! 4>&! +'.! ('GG*G'.! %;2G>CC>)1%&'.! 4&1+*%)'.! ';!

&=>()%1;!X!*;'!G=.%1;!')!('..'!.1*<';)!+-.!V*'!GY%;2G>CC>)%1;!)&>;.%)1%&'!.Y>))=;*'@!L>!FAI!

%;+*%)'! G1&.!+'.!4&1('..*.!+'! &=4>&>)%1;!('GG*G>%&'!>!+'.!C=(>;%.C'.! )&-.!.%C%G>%&'.!X!('*B!

%C4G%V*=.! +>;.! GY'CO&S1P';-.'9! C>%.! G'.! ('GG*G'.! P=;=&='.! .1;)! +'.! ('GG*G'.! ;1;!

C*G)%41)';)'.! +1;)! G>! +%22=&';(%>)%1;! '.)! )&-.! .4=(%2%V*'! +*! )%..*! G=.=@! 31;)&>%&'C';)! X! G>!

FAI! +'! )S4'! \9! G'.! ('GG*G'.! V*%! .'! &=K=4%),=G%>G%.';)! &'<%';;';)! X! G'*&! =)>)! +Y1&%P%;'! .1*.!

21&C'!+Y*;!=4%),=G%*C!+%22=&';(%=@!Tg>GG*&%!>;+!^'%G.1;9!"ff#UT7>+%.]S!')!>G@9!"ffdU@!

TEM pathologique

L>!FAI!4>),1G1P%V*'!.Y1O.'&<'!G1&.!+'!;=14G>.%'!')!+'!2%O&1.'!><'(!+'.!C1+%2%(>)%1;.!

C1&4,1G1P%V*'.!')!P=;%V*'.!(1CC*;.@!!

TEM de type 2 (Fibroses)

L'!4&1('..*.!+'!(%(>)&%.>)%1;!4'*)!>O1*)%&!X!G>!4&1+*()%1;!';!'B(-.!+'!)%..*!(1;[1;()%2!

41*&!&'C4G>('&!G'!)%..*!1&%P%;>G!')!P=;=&'&!*;'!+S.21;()%1;!1&P>;%V*'@!J%;.%9!G>!FAI!>O1*)%)!X!

G>!2%O&1.'!+>;.!('&)>%;.!1&P>;'.!41..=+>;)!*;'!1&P>;%.>)%1;!+'!)S4'!)*O*G1KG1O*G>%&'!(1CC'!

41*C1;9! 21%'9! &'%;! ')! PG>;+'!C>CC>%&'! THk>;1!')! >G@9! "ff"U@!$>;.! ('&)>%;.! (>.9! G>! 2%O&1.'!

4'*)! .'!4&1G1;P'&!')!+1;;'&!;>%..>;('!X!*;'! %;2G>CC>)%1;! (1;)%;*'9!41*<>;)!';)&>%;'&! G>!

+'.)&*()%1;!+'!GY1&P>;'!1*!*;'!)&>;.21&C>)%1;!)*C1&>G'!T7>.)>G+%!')!>G@9!"ff"U@!

TEM de type 3 (Tumorigenèse)

L>!FAI!+'!)S4'!#!.Y1O.'&<'!+>;.!G'!(1;)'B)'!+'!G>!4&1P&'..%1;!)*C1&>G'!')!GY%;<>.%1;!

C=)>.)>)%V*'@! L'.! P-;'.! %C4G%V*=.! +>;.! G>! FAI! 1;(1P=;%V*'! 4&=.';)';)! +'! ;1CO&'*.'.!

.%C%G%)*+'.! ><'(! G'.! C=(>;%.C'.! %;)'&<';>;)! +>;.! G>! +%.4'&.%1;! +'.! ('GG*G'.! =4%),=G%>G'.!

! QQ!

4&%C>%&'.!>*!(1*&.!+'!GY'CO&S1P';-.'9!C>%.!G'.!('GG*G'.!>&O1&';)!+'!;1CO&'*.'.!>G)=&>)%1;.!

P=;=)%V*'.!')!=4%P=;=)%V*'.9!;1)>CC';)!+>;.!GY'B4&'..%1;!+'.!1;(1P-;'.!')h1*!+'.!P-;'.!

.*44&'..'*&.!+'!)*C'*&!Tg>GG*&%!>;+!t'%;O'&P9!"ffbU@!

!"#$%&'($')*+,'(-.'/-(("(-.'/$%/0#-".-.'1-#2-%&'(-"#.'1#31#40&0.'$250.46-.'-&'7$7%-%&'

!"#$ %&'%&()*)#$+(,&-*&(."#$ "*$ %&'*)'/0*(12"#$ 3)."##-(&"#$ 4$ /-$ 5'&+-*('3! +'!!"#$%#$%&%'(!"#

!"#$%&'($"%)*)"%+()"(,-%."%/0#$%&"%)0,1("(,!%)2!"$345)0+"(6%"+%.0%7",+"%&"%)0,1("(,!%

!"#$%!&#'()*+,-.$+(1&&=G=.!><'(!G>!4&1P&'..%1;!)*C1&>G'!')!*;!C>*<>%.!4&1;1.)%V*'!TI1&';1K

5*';1!')!>G@9!"ffcU!T0'&G!')!>G@9!\bbeU@!

(;<=>?!U!A!&;NNC>?GDB!DVF?B!J?!5'/K!

! L>! C=)>4G>.%'! &'4&=.';)'! *;! =)>)! +'! )&>;.+%22=&';(%>)%1;! ';)&'! +'*B! )S4'.! +Y=4%),=G%*C@! L'.! #!+%22=&';).! )S4'.! +'! FAI@! L>! FAI! +'! )S4'! \! T'CO&S1P';-.'U! >O1*)%)! X! G>! 4&1+*()%1;! +'! ('GG*G'.!C=.';(,SC>)'*.'.! C*G)%41)';)'.! (>4>OG'.! +'! 21&C'&! +'! C*G)%4G'.! )%..*.! =4%),=G%>*B! .'(1;+>%&'.! 4>&! IAF@!L1&.! +'! G>! FAI! +'! )S4'! "! T+'! &=P=;=&>)%1;U9! G'.! ('GG*G'.! 4&1+*%)'.! .1;)! +'.! 2%O&1OG>.)'.! +%22=&';(%=.! V*%!.'COG';)!&'<';%&!.1*.!G'*&!21&C'!y1&%P%;'GG'z!';!GY>O.';('!+'!.%P;>*B@!L>!FAI!+'!)S4'!#!'.)!%C4G%V*='!+>;.!G>!4&1P&'..%1;!)*C1&>G'!')!GY%;<>.%1;!C=)>.)>)%V*'!Tp'%.O'&P!>;+!^'%G.1;9!"ffbU@

L'.!y!+=&%<=.!z!%;!<%<1!+'!G>!FAI!+'!)S4'!#!4'*<';)!u)&'!+'!;>)*&'!2%O&1OG>.)%V*'!1*!

C=.';(,SC>)'*.'@! T7>+%.]S! ')! >G@9! "ffdU! @! HG! '.)! )&-.! +%22%(%G'! +'! +%.)%;P*'&! G'.! ('GG*G'.!

! QR!

C=.';(,SC>)'*.'.! 4&%C>%&'.! ')! G'.! 2%O&1OG>.)'.! >*! ;%<'>*! C1G=(*G>%&'9! ';! '22')! )1*.! G'.!

+'*B! 'B4&%C';)! G>! <%C';)%;'9! .=(&-)';)! +'! G>! 2%O&1;'()%;'9! +*! (1GG>P-;'! 2%O&%GG>%&'9! +'.!

4&1)=>.'.!')!+%22=&';).!2>()'*&.!+'!(&1%..>;('@!L>!+%22=&';('!21;+>C';)>G'!';)&'!('.!('GG*G'.!

'.)!G'*&!=)>)!+'!+%22=&';(%>)%1;@!L'.!2%O&1OG>.)'.!.1;)!+'.!('GG*G'.!)&-.!+%22=&';(%='.9!C>%.!G'.!

('GG*G'.! C=.';(,SC>)'*.'.! 4&%C>%&'.! 'B4&%C';)! +'.! C>&V*'*&.! +'! 4G*&%41)';('! ')! .1;)!

(>4>OG'.! +'! +1;;'&! ;>%..>;('! X! +'! ;1CO&'*B! )S4'.! ('GG*G>%&'.@! L'.! 2%O&1OG>.)'.! .1;)!

(>4>OG'.!+'!C%P&'&!')!+'!&'[1%;+&'!G>!(%&(*G>)%1;!.>;P*%;'!1*!GSC4,>)%V*'!4>&!%;)&><>.>)%1;9!

C>%.! G'*&!.*&<%'!'.)!P=;=&>G'C';)!+'!(1*&)'!+*&='!')!;'!+1;;'!4>.! G%'*!X! G>! 21&C>)%1;!+'!

;1+*G'.!C=)>.)>)%V*'.!.'(1;+>%&'.!Tg114!')!>G@9!\bbcU@!

!

! Qc!

II. PROCESSUS CELLULAIRE

CONDUISANT A LA TEM

A.LES ACTIVATEURS DE LA TEM

!

L>!G%.)'!P=;=&>G'!+'.!(>;+%+>).!%C4G%V*=.!+>;.!G>!&=P*G>)%1;!+'!G>!FAI!'.)!)&-.!G1;P*'/!

+%<'&.! .)%C*G%.! (1CC'! G'! F8_Ka9! G'! _8_9! GYA8_9! GYH8_9! GYD8_9! G'!0$8_9! G'.!1'.)&1P-;'.9!t;)9!

N,,9! G'.! (S)1]%;'.! %;2G>CC>)1%&'.9! GY,S41B%'9! G'.! 1;(1P-;'.!7>.E\"9! A&O5"9! 4R#!C*)='!')(!

TF,%'&S!')!>G@9!"ffbU@!L'.!>()%<>)'*&.!+'!G>!FAI!(1CC'!G'!F8_Ka9! G'!F^_K`!')! GYD8_!4&1+*%).!

4>&! G'.! ('GG*G'.! .)&1C>G'.! 1*! 4>&! G'.! ('GG*G'.! )*C1&>G'.! %;+*%.';)! GY>()%<>)%1;! +'! 2>()'*&.!

)&>;.(&%4)%1;;'G.! +'! G>! FAI! TF,%'&S! >;+! NG''C>;9! "ffcU! (1C4&';;';)! G'.!C'CO&'.! +'! G>!

2>C%GG'!!ODLD!TO>.%(!,'G%4KG114K,'G%B!2>C%GSU9!8N3!T811.'(1%+U9!p_D!Tl%;PK2%;P'&!AKO1B!O%;+%;P!

,1C'1O1BU! T0'%;>+1!')!>G@9!"ffdU@!J*!(1*&.!+'!('))'!),-.'9!4>&C%.!+%<'&.!>()%<>)'*&.!+'! G>!

FAI9! ;1*.! >GG1;.! ;1*.! %;)=&'..'&! 4G*.! 4>&)%(*G%-&'C';)! >*! ! &ZG'! +*! F8_Ka! ! ')! +*! F^_K`!

T2>()'*&! G%=!X! GY%;2G>CC>)%1;U!+>;.! GY%;+*()%1;!+'! G>!FAI@!A;!'22')9!+>;.!;1)&'!4&1[')9!;1*.!

><1;.!*)%G%.=! G>! G%P;='!+'!(>;('&!4*GC1;>%&'!JRQb!+1;)! GY'B41.%)%1;!>*B!(S)1]%;'.!F^_K`!')!

F8_Ka!!4'&C')!GY%;+*()%1;!+'!G>!FAI!+'!C>;%-&'!&=<'&.%OG'@!

)

TGF- β

L>! 2>C%GG'! F8_Ka! (1C4&';+! )&1%.! %.121&C'.! +'! F8_K! a! TF8_KaK\9! K"9! K#U9!')! +W>*)&'.!

(S)1]%;'.! %C4G%V*='.! +>;.! G>! +%22=&';(%>)%1;! ')! G>! 4&1G%2=&>)%1;! ('GG*G>%&'! (1CC'! G'.! 5I0!

TO1;'! C1&4,1P';')%(! 4&1)'%;.U9! G'.! %;,%O%;'.! ')! G'.! >()%<%;'.@! Ti*! ')! >G@9! "ffbU@! L'.! )&1%.!

%.121&C'.! +*! F8_Ka! .1;)! (1+='.! 4>&! +'.! P-;'.! +%.)%;().9! V*%! (1;.'&<';)! )1*)'21%.! df�!

+Y,1C1G1P%'!';)&'!'*B!TI>..>P*=9!\bbeUT$'&S;(]!')!>G@9!"ff\UT3,%;!')!>G@9!"ffQUTI>..>P*=9!

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! Qd!

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p53 dans la TEM :

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(>+,=&%;'! T3,>;P! ')! >G@9! "f\\>U@! L>! .*44&'..%1;! +'! 4R#! >*PC';)'! >*..%! G>! )&>;.G1(>)%1;!

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(>)=;%;'!><'(!iJEb#b!>O&1P'!GY%;+*()%1;!+'!G>!FAI!4>&!G>!.*44&'..%1;!+'!4R#!Tt>;P!')!>G@9!

"f\#U@! L1&.! +*! )&>%)'C';)! ><'(! G'! F8_Ka9! G>! +%C%;*)%1;! +'! GY'B4&'..%1;! +'! 4R#! %;+*%)! G'!

4,=;1)S4'!+'!FAI!')!G'.!4&14&%=)=.!.1*(,'.@!J%;.%9! GY>*PC';)>)%1;!+'!4R#!+>;.!('!C1+-G'!

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G'.! %;+*()'*&.! +'! G>! FAI@! L>! +%C%;*)%1;! +'! GY'B4&'..%1;! +'! ('.! C%7.! >22'()'! G>! FAI! 4>&!

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41*&!.*44&%C'&! G'.!C=)>.)>.'.!4*GC1;>%&'.!+>;.! G'!C1+-G'!+'.!B=;1P&'22'.@!I>%.!J0Q!'.)!

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Les homologues de p53 :

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3. IMMUNOSURVEILLANCE ET

EVASION TUMORALE

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NUCLEAR FACTOR-KAPPA B

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fait l’objet d’un article scientifique dans Journal of Experimental & Clinical Cancer Research

en 2015. (Asgarova et al., ”Epithelial-Mesenchymal Transition (EMT) regulates PD-L1

expression in non-small cell lung carcinoma: a role for IKKε”, en soumission.)

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Epithelial-Mesenchymal Transition (EMT) regulates PD-L1 expression in

non-small cell lung carcinoma: a role for IKKε.

Asgarova A1-3

, Asgarov K1-3

, Galaine J1-3

, Guenat D1-4

, Mougey V 1-4

, Queiroz L1-4

, Pallandre

JR1-3

, Bouard A1-3

, Balland J1-3

, Adotevi O1-3

, Godet Y1-3

, Hervouet E3, Borg C

1-5.

1 INSERM unit 1098, 8 rue du Docteur Jean-François-Xavier Girod BP 1937 25020

Besançon Cedex France. 2 Clinical Investigation center-Biotherapy, 3 bd Fleming, F-25030 Besançon Cedex, France

3 University of Franche Comté, Besançon, France

4 Etablissement Français du Sang, UMR1098, 8 rue du Docteur Jean-François-Xavier Girod

BP 1937 25020 Besançon Cedex France. 5

University Hospital of Besançon, Department of Medical Oncology, 3 bd Fleming, F-25030

Besançon Cedex, France

Corresponding author: Christophe Borg, 8, rue du Docteur Jean-François-Xavier Girod BP

1937 25020 Besançon Cedex France. Tel : 33 3 81 66 93 21 ; fax : 33 3 81 66 97 08 ; email :

christophe.borg@efs.sante.fr

Keywords: epithelial-mesenchymal transition; IKKε; NF-κB; death receptors; PD-L1; A549;

lung cancer, cancer

Figure 1. A549 model.

Figure 2. Regulation of death receptors and immune checkpoint inhibitors on A549 during EMT.

Figure 3. TNF-α and TGF-β1 cooperate to promote PD-L1 expression during EMT(reversible).

Figure 4. PD-L1 expression is not regulated by conventional EMT transcriptional regulators in A549.

Figure 5. Influence of TNF-α and TGF-β1-mediated EMT on NFk-β signaling.

Figure 6. Role of IKKε in the regulation of PD-L1 by EMT in A549.

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Abstract:

Epithelial-mesenchymal transition (EMT) is a factor of poor prognosis in several

cancers. Tumor cells, which undergo EMT acquire increased capacities of proliferation,

invasion and have the ability to generate metastases. Invading cells must escape the immune

system during their systemic migration, before metastasis initiation. To escape the immune

system, cancer cells may induce tolerance or resist destruction by immune effectors via

multiple mechanisms such as: release of inhibitory proteins (IL-10, TGF, HLA-G), expression

of immune checkpoint inhibitors (PDL-1, Gal-9), loss of NK cell receptor activating ligands

(ULBPs, MICA/B) or Major Histocompatibility Complex, decrease of death receptors (DR4,

DR5, Fas). We hypothesized that EMT might control immune checkpoint inhibitors, then

promoting immune evasion. In the current study, we investigated the regulation of PD-L1

during EMT in non-small cell lung carcinoma (NSCLC). EMT was generated in A549

NSCLC cell line by exposition to TNF-α and TGF-β1. Death receptor (DR4, DR5 and Fas)

and ligands (FasL and TRAIL) expression were not modified during EMT process. Similarly,

EMT did not influence the levels of NK cell activating or inhibitory molecules. By contrast,

PD-L1 but not PD-L2 nor galectin 9 expressions was up-regulated during cytokine-driven

EMT in a reversible manner. The EMT-related transcription factors Snail and Zeb1 were not

involved in PD-L1 regulation. Then, we analyzed the role of NF-κβ. The induction of EMT in

A549 enhanced the expression of IKKε in a TNF-α dependent fashion. Using two different

pharmacological inhibitors and IKKε siRNA, we evidenced a role of this molecular pathway

in PD-L1 regulation.

!

Count:

Title: 15 words

Abstract: 250 words

Text: 2902 words (excluding abstract, legends and references)

Pages: 31

Figures: 6

References: 56

!

! \#R!

Introduction

Epithelial-mesenchymal transition (EMT) is a highly conserved cellular process that allows

epithelial cells to convert to mesenchymal cells (Kalluri and Weinberg, 2009). The loss of E-

cadherin expression is a crucial step in EMT and a hallmark of mesenchymal phenotype,

whereas Vimentin is a canonical marker for detecting fully transitioned epithelial cells and

acquisition of fibroblastic-like phenotype. EMT is involved in different physio-pathological

contexts including: embryonic and organ development (type 1 EMT), tissue regeneration and

fibrosis (type 2 EMT), or carcinoma progression (type 3 EMT) (Kalluri and Weinberg, 2009).

Several signaling pathways contribute to EMT regulation (Thiery et al., 2009). Oncogenesis,

hypoxia or exposition to chronic inflammation are the main environmental conditions

promoting the ability of tumor cells to undergo EMT (López-Novoa and Nieto, 2009). TGF-

β1, TNF-α, HGF, EGF, PDGF, Wnt or NOTCH ligands are soluble factors which can control

mesenchymal phenotype acquisition during cancer progression (Thiery and Sleeman, 2006)

(Heldin et al., 2012). The acquisition of a complete mesenchymal program relies on the

expression of specific transcription factors such as Zeb, Snail, Slug, Twist, which repress E-

cadherin, induce the transcription of molecules involved in cytoskeleton regulation and

promote secretion of metalloproteinase and invasion (Garg, 2013). Tumor cells, which

undergo EMT, acquire capacities of proliferation, migration and resistance to apoptosis. By

co-opting a program involved in embryonic development, carcinoma cells are able to invade

normal tissues and to induce metastases. EMT also confers to carcinoma cells, stem cell like

properties indispensable to clonal expansion and initiation of metastases (Scheel and

Weinberg, 2012). Altogether, EMT is one of the major molecular mechanisms carried out

during oncogenesis to enable cancer progression. One crucial step of oncogenesis is the

acquisition by cancer cells of the ability to evade the immune system (Hanahan and

Weinberg, 2011) (Gajewski et al., 2013). Recent clinical advances in immunotherapy

demonstrated that some cancers with established lymphocyte infiltrates, express immune

checkpoint inhibitory molecules, such as PD-L1, to allow their progression. Several studies

suggested that PD-L1 status may be a new predictor of poor prognosis for patients with lung

cancers (Chen et al., 2009), (Chen et al., 2012c), (Shi et al., 2013). In these patients, treatment

with anti-PD-L1 or anti-PD-1 restored effective antitumor immunity and induced long lasting

objective responses, demonstrating the pivotal role of such immune inhibitory signaling in

oncogenesis.

!

! \#c!

Then, we hypothesized that the expression of immune checkpoint inhibitors might be

specifically regulated during EMT to allow invasion and immune escape. To investigate this

issue, we selected a model of reversible EMT based on TNF-α and TGF-β1 treatment of the

cell line A549. Expression of death receptors or ligands, NK cell activating or inhibitory

molecules, as well as immune checkpoint inhibitors were analyzed according the EMT status.

We observed that induced EMT in NSCLC does not modify NK cell activating or inhibitory

molecules as well as death receptors or ligands. By contrast, we showed that PD-L1 was up-

regulated during EMT in a reversible manner. PD-L1 expression was not correlated to EMT

specific transcription factors, STAT1 or canonical NF-κβ pathways. By contrast, we

evidenced that the control of PD-L1 expression during EMT involved IKKε.

!

! \#d!

Results

Regulation of death receptors and NK cell-activating molecules on A549 during EMT.

In order to assess how EMT influences the recognition of tumor cells by lymphocytes during

invasion, we selected a reversible model of EMT. In vitro induction of epithelial-

mesenchymal transition in A549 cell line has been reported previously (Kasai et al., 2005),

(Liu, 2008), (Yamauchi et al., 2010), (Kawata et al., 2012), (Saito et al., 2013). For this

purpose, A549 cell line was exposed to TNF-α and TGF-β1 during 5 days. This treatment

allowed this epithelial cell line to acquire the feature of mesenchymal tumor cells (Figure 1A).

Removal of TNF-α and TGF-β1 led to the restoration of an epithelial phenotype within 5 days

(Figure 1A). The EMT status was confirmed by western blotting showing that TNF-α and

TGF-β1 treatment repressed E-cadherin and induced overexpression of Vimentin (Figure 1B).

Losses of E-cadherin and of the membrane distribution of β-catenin were also confirmed by

confocal microscopy (Figure 1C). Similarly, TNF-α and TGF-β1 induced a reversible loss of

EPCAM (Figure 1D). EMT phenotype conferred by exposition to cytokine combination was

also associated with an enhanced invasive capacity of A549 compared to the invasion ability

of A549 exposed to TNF-α or TGF-β1 alone (Figure 1E).

Effector immune cells can eliminate carcinoma cells throughout different mechanisms: one of

these mechanisms is the production of pro-apoptotic ligands, which belong to the tumor-

necrosis factor (TNF) superfamily. TNF-related apoptosis-inducing ligand (TRAIL) and Fas

ligand (FasL) are two of these pro-apoptotic ligands. They trigger extrinsic apoptosis through

the activation of “death receptors”, Death Receptor 4 (DR4) / Death Receptor (DR5) and Fas,

respectively. Then, we first assessed the expression of DR4, DR5 and Fas on A549 exposed

or not to TNF-α and TGF-β1. We could observe that DR and Fas expressions were not

significantly modified during the acquisition of mesenchymal phenotype by A549 (Figure

2A). Another mechanism involved in the eradication of tumor cells during

!

! \#e!

immunosurveillance is the recognition of NKG2D-ligand by CD8 T lymphocytes or NK cells

(Deng et al., 2015), (Diefenbach et al., 2000), (Diefenbach et al., 2001), (Groh et al., 2002).

(Diefenbach et al., 2003). Accordingly, previous experiments were reproduced and the

expression of NKG2D ligands was assessed by flow cytometry. TNF-α and TGF-β1 did not

influence the expression of the NKG2D ligands MICA, MICB, ULBP1-3 (Figure 2B). Of

note, we did not observe in these experiments any significant modification in MHC class I

(Figure 2B) or HLA-G expression (Figure S1A). Moreover, the modulation of molecules

regulating the recognition of tumor cells by NK was unlikely. Indeed, a 5 days TNF-α and

TGF-β1 treatment of A549 during 5 days did not hampered the capacity of activated NK to

recognize and kill A549 nor to produce IFN-γ following cocultures with this cell line (Figure

S1B).

Role of Cytokine-mediated EMT in immune checkpoint inhibitor regulation on A549.

The next set of experiments was performed to investigate the modulation of TIM03 and PD-1

ligands in A549 according to EMT status. Flow cytometry experiments showed that TNF-α

and TGF-β1 treatment did not influence the expression of the TIM03 ligands Galectine 9 or

CEACAM1 (CD66), while EMT induction, as monitored by the loss of EPCAM, led to the

up-regulation of PD-L1 (Figure 3A). PD-L2 was not expressed in this model (Figure 3A). PD-

L1 expression disappeared after removal of TNF-α and TGF-β1 (Figure 3A). The regulation

of PD-L1 by exposition to TNF-α and TGF-β1 involved pdl1 transcription as confirmed using

RT-PCR (Figure 3B). These results indicate that cytokine-mediated EMT promotes the

expression of PD-L1.

TNF-α and TGF-β1 cooperate to promote PD-L1 expression during EMT

We next sought to determine which of TNF-α or TGF-β1 signaling contributes to the

regulation of PD-L1. For this purpose, A549 cells were treated with TNF-α, TGF-β1 or with

!

! \#b!

the combination during 5 days. As previously described (Liu, 2008),(Yamauchi et al., 2010),

(Saito et al., 2013), TNF-α or TGF-β1 treatment alone failed to drive the mesenchymal

transformation of A549 in short term cultures (Figure 3C). Moreover, treatment with each

cytokine alone, used during 5-14 days, was not able to induce PD-L1 expression. By contrast,

only cytokine combination promoted significant PD-L1 expression (Figure 3C).

PD-L1 expression is not regulated by conventional EMT transcriptional regulators in A549

The increased transcription of PD-L1 during cytokine-induced EMT, prompted us to

characterize the expression of EMT-related transcriptional regulators in A549. Western

blotting experiments showed an increased expression of main transcription factors of EMT,

Zeb1 and Snail in A549 treated by TNF-α and TGF-β1(Figure 4A). RT-PCR analyses

confirmed the expression of Snail and Zeb1 in A549 (Figure 4B). Of note, TNF-α alone

increased Zeb1 while TGF-β1 exposition enhanced Snail expression ruling out a direct role of

these transcriptional modulators in PD-L1 regulation (Figure 4A). Moreover, Snail

transfection in A549 did not induce PD-L1 even when this cell line was exposed to TNF-α or

TGF-β1 (Figure 4C).

Influence of TNF-α and TGF-β1-mediated EMT on NFk-β signaling

In order to decipher the mechanisms implicated in the control of PD-L1 during cytokine-

induced EMT, we first analyzed the transcription factor DNA binding sites within PD-L1

promoter using matinspector. NF-κβ was the main transcription factor, previously described

as promoting EMT (Huber et al., 2004), (Radisky and Bissell, 2007), (Cheng et al., 2011b),

(Li et al., 2012b), (Kumar et al., 2013) and displaying a binding site in PD-L1 promoter.

Then, we decided to characterize NF-κβ unit expression during cytokine-induced EMT in

A549. We could observe an increase of p52 NF-κβ sub-unit in mesenchymal cells while RelA

expression was not significantly modified. We also identified an increase of the non-canonical

IKKε proteins (Figure 5A). Of note, we also observed that exposition to TNF-α and TGF-β1

!

! \Qf!

did not promote RelA nuclear translocation (Figure S2A). Consequently, the next set of

experiments was designed to investigate the role of p52 NF-κβ sub-unit in the control of PD-

L1 during EMT. JSH23, a pharmacological inhibitor of p52, was used to prevent p52

expression in A549 cells treated with TNF-α and TGF-β1. JSH-23 selectively blocks nuclear

translocation of active NF-кB without affecting the process of IkB degradation and suppress

its binding to the DNA consensus sequence (Shin et al., 2004), (Kumar et al., 2011). As

previously described, JSH23 inhibited the induction of NF-κβ in A549 following cytokine-

induced EMT (Figure 5B). Nevertheless, JSH23 did not prevent PD-L1 expression in these

experiments (Figure 5C). A potential role of p52 NF-κβ subunit was also excluded since

transfection of p52 (Figure 5D) did not modify the expression of PD-L1 in A549 cultured in

complete medium, as well as in cultures containing TNF-α or TGF-β1 (Figure 5E).

Altogether, these experiments ruled out a potential role of p52 NF-κβ subunit in PD-L1

regulation during cytokine-mediated EMT.

Role of IKKε in the regulation of PD-L1 by EMT in A549

Since previous experiments unraveled an increased expression of IKKε in A549 treated with

TNF-α and TGF-β1, the role of this signaling pathway in PD-L1 expression was investigated.

Accordingly, IKKε was genetically transferred into A549 cancer cell lines (Figure 6A).

Overexpression of IKKε sustained the up-regulation of PD-L1 in A549 treated with TNF-α

but not in steady state conditions and not after exposition to TGF-β1 (Figure 6B). The precise

role of IKKε was further analyzed using two different IKKε pharmacological inhibitors. A549

cells were treated with BX795 and MRT67307 before exposition to TNF-α and TGF-β1

during 5 days. Both IKKε pharmacological inhibitors prevented PD-L1 expression after TNF-

α and TGF-β1 treatment (Figure 6C). Moreover, similar results were achieved using IKKε

specific siRNA (Figure 6D).

!

! \Q\!

Discussion

EMT is a complex reprogramming of epithelial cells playing a pivotal role in tumor invasion,

acquisition of stemness properties and metastasis development. In the present study, we

questioned the influence of EMT in PD-L1 regulation.

EMT is controlled by transcriptional repressors recruited to the E-box elements of E-cadherin

promoter. We selected a model were EMT can be induced in a reversible manner in order to

mimic the invasion phase leading to metastasis formation. As previously described, we

observed that TNF-α and TGF-β1 synergized to promote EMT of A549. In this model,

(Kumar et al., 2013) Snail and Zeb1 were overexpressed in A549 following TGF-β1 used

alone or in combination with TNF-α (Figure 4A and B). In the present study, we showed that

EMT phenotype conferred by TGF-β1 and TNF-α to A549 was associated with the up-

regulation of PD-L1, in line with the requirement for an invading tumor cell to evade the

immune system. Of note, exposition to TNF-α or TGF-β1 alone did not induce a significant

expression of PD-L1. Moreover, snail transfection did not promote PD-L1 on A549,

suggesting that a synergism between TGF-β1 and TNF-α signalling rather than a direct impact

of EMT-derived transcription factors might be required to control PD-L1 in this setting.

Hypoxia, interactions with stromal cells such as cancer associated fibroblasts and

mesenchymal stem cells, or inflammation are elements of the tumor microenvironment

promoting EMT (Thiery and Sleeman, 2006). Among growth-factors and cytokines involved

in this dedifferentiation process, TGF-β1 was shown to be of particular importance (Xu et al.,

2009), (Korkaya et al., 2011). Indeed, TGF-β1 controls the expression of EMT-related

transcription factors such as SNAIL, ZEB and TWIST1 (Xu et al., 2009).

TNF-α is another cytokine produced by hematopoietic cells such as M2 macrophages within

tumor microenvironment and exerting a promoting role on EMT (Gao et al., 2012) (Scheel et

!

! \Q"!

al., 2011). TNF-α stimulates nuclear factor kappa β (NF-κB) in cancer cells and potentiates

the ability of TGF-β1 to induce EMT (Scheel et al., 2011) (Kawata et al., 2012).

NF-κB transcription factor family is composed of 5 subunits: RelA, RelB, c-Rel, NF-κB1

(p105/p50), NF-κB2 (p100/p52). NF-κB signaling is an important component of the

molecular network induced by inflammation in cancer cells (Karin, 2006). Indeed, Huber MA

et al showed that NF-κB signaling is required for initiation and maintenance of TGF-β1

driven EMT in breast carcinoma (Huber et al., 2004). In this model, IκκB promotes TWIST1

expression leading to the acquisition of EMT phenotype and cancer stem cell properties. It

was also previously reported in A549 model, that mesenchymal NSCLC display a

constitutively active NF-κB signaling (Kumar et al., 2013). Then, the role of NF-κB in PD-L1

regulation was addressed. We first observed that cytokine-driven EMT increased NF-κB2

(p100/p52) in A549, but not RelA (Figure 5). Nevertheless, NF-κB2 pharmacological

inhibition or genetic transfer did not influence the regulation of PD-L1 (Figure 5).

IκB kinase ε is a non-canonical IKK, which plays a pivotal role as a regulator of innate

immunity. Known functions of IKKε include the modulation of NF-κB and interferon

signaling after pattern recognition receptor activation (Ng et al., 2011b). Moreover, IKKε

activation might also results from Toll-like receptor independent mechanisms (Hutti et al.,

2009) and contributes to bridge inflammation and oncogenesis (Shen and Hahn, 2011). IKKε

was overexpressed in cytokine-induced EMT in our study (Figure 5).

It was previously established that the role of IKKε in antiviral responses requires serine 708

phosphorylation of STAT1 (Tenoever et al., 2007). It was further evidenced that IKKε

phosphorylates serine residues of IRF1 and IRF3 to promote their nuclear translocation and

transcriptional activity (Fitzgerald et al., 2003) (Hemmi et al., 2004).

The regulation of PD-L1 expression became an issue of growing importance regarding the

clinical results achieved with anti-PD-1/PD-L1 immunotherapy (Pardoll, 2012), (Brahmer et

!

! \Q#!

al., 2012), (Topalian et al., 2012), (Drake et al., 2014) (Nguyen and Ohashi, 2015). While PD-

L2 is mostly expressed on dendritic cells and macrophages, PD-L1 expression was reported

on tumor cells (Dong et al., 1999), (Freeman et al., 2000) (Tseng et al., 2001) (Latchman et

al., 2001) but also on myeloid cells infiltrating cancer microenvironment (Noman et al.,

2014). PD-L1 promoter contains hypoxia-response element and HIF-1α but not HIF-2α

promotes PD-L1 expression in tumor microenvironment (Noman et al., 2014). The

transcription of PD-L1 is also up-regulated by IFN-γ in a STAT1/3 dependent fashion (Loke

and Allison, 2003). Furthermore, IRF-1 is required for the constitutive and IFN-γ inducible

PD-L1 expression (Lee et al., 2006a).

Silencing of IRF-1 transcription inhibits PD-L1 and PD-L2 induction during DC maturation,

while leaving unaltered MHC class II and levels of costimulatory molecules (Martínez et al.,

2014).

Here, we did not observe any influence of EMT on the expression or nuclear localization of

STAT1 or IRF1, 3 in A549 exposed to TNF-α and TGF-β1 (data not shown). It was

previously reported that IKKε phosphorylates the COOH terminal domain of IRF1 (Sgarbanti

et al., 2014). IRF1 phosphorylation was shown to prevent its interactions with the RelA

subunit of NF-κB. In our study, EMT of A549 mediated by cytokines did not increase the

levels and nuclear localization of IRF1 following TNF-α and TGF-β1 exposition.

ERK/p38 MAP-kinases and PI3K are other signaling pathways, which were demonstrated as

involved in PD-L1 regulation in DC. In multiple myeloma, blocking ERK1/2 but not p38

MAP-kinases, PI3K nor NF-κB influenced PD-L1 regulation (Liu et al., 2007b). In addition,

while IFN-γ upregulates both PD-L1 and MHC class I on tumor cells, ERK1/2 inhibitors

increase tumor-specific cytotoxic lymphocyte activity through MHC class I modulation

without affecting PD-L1 expression (Mimura et al., 2014). In A549, ERK1/2 inhibition did

not affect TNF-α and TGF-β1 driven EMT and PD-L1 expression (data not shown).

!

! \QQ!

Mesenchymal cells are endowed with properties of proliferation and invasion, but are also

able to resist to extrinsic apoptosis triggered by DR4, DR5 and Fas activation. Few studies

(Knutson et al., 2006 ; Kudo-Saito et al., 2009 ; Santisteban CR 2009 ; Reiman -review- JM

et al 2010 ) have already suggested that EMT foster cancer progression also by acting on

immunosuppression and immunoresistance mechanisms allowing tumors to escape immune

surveillance. A previous work has demonstrated that EMT is involved in the induction of

immunosuppression (Kuto-Saido Can Cell 2009): mesenchymal cells are able to induce

regulatory T cells and to impair dendritic cells in vitro and in vivo partly through TSP1

production. Inversely, elements of the immune system can act as inducers of EMT

(Santisteban Can Res 2009): CD8 T cells can stimulate mammary epithelial tumor cells to

undergo EMT. In the present study, we established another link between EMT and immune

escape through the ability to evade immune functions by PD-L1 expression on tumour cells.

The regulation of PD-L1 on cancer cells might depend on inflammatory stimuli since

cytokine-mediated EMT but not Snail-mediated EMT promoted PD-L1 expression. In this

process, IKKε sustains the crucial role of inflammation during EMT to control PD-L1.

!

! \QR!

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Conflict of interest

Acknowledgments

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References

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En conclusion, nos travaux montrent que le programme de la TEM utilisé lors de la

phase d’invasion des cellules tumorales, induit l’expression de PD-L1. Nous avons observé

que ce processus est spécifique car les autres voies de signalisation de l’échappement au

système immunitaire explorées, ne sont pas modulées lors de la TEM induite par les cytokines

dans A549. Enfin, nous avons mis en évidence le rôle de la protéine IKKε dans ce modèle.

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http://www.genecards.org/cgi-bin/carddisp.pl?gene=IKBKE

http://swissmodel.expasy.org/repository/?pid=smr03&mid=md7cb57dfd70769758593c4ff888

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