銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

浠婂ぉ锛岀檶鐥囧厤鐤不鐤楀啀娆¤繋鏉ラ噸澶х獊鐮达紒

钁楀悕鍗庝汉绉戝瀹堕檲鍒楀钩鏁欐巿棰嗗鐨勫洟闃熷彂鐜帮紝鑲跨槫鑳介€氳繃涓€鏉″叏鏂扮殑閫氳矾鎶戝埗鍏嶇柅绯荤粺锛屽畬鎴愬厤鐤€冮€搞€傝偪鐦ゅ伔鍋疯俯浣忎簡鍏嶇柅绯荤粺鍙︿竴涓埞杞︼紝鑰岃繖绉嶇幇璞″湪澶氱鐧岀棁涓兘瀛樺湪銆�

杩欎釜鍙戠幇鎴栬鍙互瑙ｉ噴鐜版湁鍏嶇柅鐤楁硶鍦ㄥ緢澶氭偅鑰呬腑鏃犳硶鍙戞尌浣滅敤鐨勫師鍥犮€傛洿閲嶈鐨勬槸锛�瀵逛簬鑲跨槫鏂板瀷鍏嶇柅閫冭劚鏈哄埗鐨勮В鏋愶紝灏嗗府鍔╂垜浠敾鍏嬫洿澶氱被鍨嬬殑鐧岀棁锛屼娇瓒婃潵瓒婂鏇村鐨勬偅鑰呭彈鐩婏紒杩欓」鎴愭灉鍙戣〃鍦ㄥ浗闄呴《绾у鏈湡鍒娿€婄粏鑳炪€嬩笂[1]銆�

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

闄堝垪骞虫暀鎺�

鍦ㄨ偪鐦ゅ厤鐤鍩熸繁鑰曟暟鍗佸勾锛岄檲鏁欐巿娣辩煡鍏嶇柅娌荤枟杩樺瓨鍦ㄥ緢澶氶棶棰樻病鏈夎В鍐炽€�

鈥滃彧鏈�25%-30%鐨勮偪鐦ら噰鐢≒D-1/PD-L1閫氳矾鏉ユ姂鍒跺厤鐤弽搴旓紝鑰屽叾浠栬偪鐦ょ敤浜嗗彟澶栫殑鍒嗗瓙閫氳矾鎴栨満鐞嗘潵閫冭劚鍏嶇柅鍙嶅簲鐨勬敾鍑伙紝瀵逛簬杩欎簺鏈虹悊鎴戜滑鐭ヤ箣鐢氬皯銆�鈥濋檲鍒楀钩鏁欐巿璇撮亾[2]銆�

鑰屼粬鐨勫洟闃熶篃姝ｆ湞杩欎釜鏂瑰悜鍔姏锛屽鎵綪D-1-PD-L1绛夐€氳矾涔嬪鐨勫厤鐤€冮€告満鍒躲€�

闄堟暀鎺堝皢鐩厜閿佸畾鍦═缁嗚優鐨勪竴涓厤鐤鏌ョ偣鍙椾綋鈥斺€擫AG-3锛堟穻宸寸粏鑳炴椿鍖栧熀鍥�3锛変笂銆傝繖涓狶AG-3鍙椾綋鏄厤鐤粏鑳炵殑鍙︿竴涓€�鍒硅溅鈥濆垎瀛愶紝瀹冭兘鎶戝埗T缁嗚優鐨勫娈栥€佹椿鍖栧拰鏁堝簲鍔熻兘锛岀淮鎸佷綋鍐呯殑鍏嶇柅绋虫€乕3]銆�

浣嗘槸锛岀洰鍓嶄汉浠繕涓嶇‘瀹歀AG-3鐨勪富瑕侀厤浣撴槸浠€涔堬紝涔熷氨鏄杩樹笉鐭ラ亾杩欎釜鍒硅溅鏄皝韪╃殑銆�鎴戜滑闇€瑕佹壘鍒拌繖涓厤浣擄紝鍥犱负瀹冨彲鑳芥垚涓鸿偪鐦ょ殑甯嚩銆�

浣嗘槸瑕佹壘鍒拌繖涓綔鍦ㄧ殑甯嚩鍙笉瀹规槗銆�

宸ユ鍠勫叾浜嬶紝蹇呭厛鍒╁叾鍣ㄣ€�

闄堝垪骞冲洟闃熷紑鍙戝嚭浜嗕竴涓熀浜庡熀鍥犵粍鐨勫彈浣撶瓫閫夊钩鍙扳€斺€擥SRA[4]锛屾潵瀵绘壘鈥滃府鍑垛€濈殑韪抗銆�

杩欎釜GSRA鎶€鏈殑鍘熺悊锛屾槸灏嗕汉绫荤殑鍒嗘硨铔嬬櫧鍔犱笂涓€涓法鑶滅粨鏋勫煙锛屼娇鍏惰兘鍦ㄧ粏鑳炶〃闈腑琛ㄨ揪锛岃€屾墍瑕佸鎵剧殑閰嶄綋涔熼殣钘忓湪鍏朵腑銆�鑻ラ厤浣撹兘涓庡甫鏈夋姉浣撴爣绛剧殑LAG-3鍙椾綋鐩镐簰浣滅敤锛屽氨鑳介€氳繃鎶椾綋寮曡捣鑽у厜鍙樺寲锛岃€岃繖绉嶅彉鍖栬兘鐢ㄦ縺鍏夋壂鎻忎华妫€娴嬪埌銆�

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

GSRA绯荤粺

閫氳繃杩欎釜鎶€鏈钩鍙帮紝闄堟暀鎺堝洟闃熷彂鐜颁竴涓彨FGL1鐨勮泲鐧戒笌LAG-3鍙椾綋缁撳悎寰堢揣瀵嗐€�

闅忓悗锛岀爺绌朵汉鍛樺杩欎釜FGL1铔嬬櫧鐨勫姛鑳借繘琛屼簡妫€娴嬨€�

褰撶敤FGL1铔嬬櫧鍘荤粨鍚圱缁嗚優琛ㄩ潰鐨凩AG-3鍙椾綋锛�纭疄鍙戠幇T缁嗚優鐨勫娈栧彈鍒颁簡鎶戝埗锛屽厤鐤椿鎬т篃鍙楀埌浜嗗奖鍝嶃€�

涓嶈繃锛孎GL1铔嬬櫧姣曠珶鏄満浣撹嚜韬〃杈剧殑铔嬬櫧[5]锛屽畠鍦ㄦ満浣撳唴鏄湁鍏朵綔鐢ㄧ殑銆�

褰撶鐮斾汉鍛樺皢鍦ㄥ皬榧犱腑灏咶GL1鍩哄洜鏁查櫎鏃讹紝鍙戠幇鍦ㄨ繖浜涘皬榧犲湪鑰佸勾鏃跺彂鐢熶簡鑷彂鎬х毊鐐庯紝杩欐槸涓€绉嶈嚜韬厤鐤柧鐥呫€傝繖琛ㄦ槑FGL1铔嬬櫧鍦ㄦ満浣撲腑鏄彂鎸ュ厤鐤皟鑺備綔鐢ㄧ殑锛岀淮鎸佽€佸勾鐨勫厤鐤ǔ鎬併€�

浣嗘槸锛�FGL1铔嬬櫧鐨勮繖绉嶅厤鐤姂鍒跺姛鑳芥槸鍚︿細琚偪鐦ゅ埄鐢ㄥ憿锛�

鍦↙AG-3鎴朏GL1鍩哄洜鏁查櫎鐨勫皬榧犵Щ妞嶈偪鐦ゅ悗锛屽彂鐜拌偪鐦ょ敓闀挎槑鏄惧彈鍒颁簡鎶戝埗銆�杩欒鏄嶧GL1- LAG-3閫氳矾纭疄鍦ㄨ偪鐦ょ殑鍙戝睍涓彂鎸ヤ簡浣滅敤銆�

褰撶敤鍗曟姉鎶戝埗鑲跨槫灏忛紶鐨凢GL1铔嬬櫧鎴朙AG-3铔嬬櫧鏃讹紝涔熻兘璧峰埌鎶戝埗鑲跨槫鐨勬晥鏋溿€傝€屽皢T缁嗚優娑堥櫎鍚庯紝杩欑鎶戝埗灏变笉瀛樺湪浜嗐€�

杩欒繘涓€姝ヨ瘉鏄庝簡鑲跨槫鑳介€氳繃FGL1铔嬬櫧婵€娲籘缁嗚優鐨凩AG-3鍙椾綋锛屾姂鍒禩缁嗚優锛屽疄鐜板厤鐤€冮€�銆傝€岃繖涓€杩囩▼鏄嫭绔嬩簬宸茬煡鐨勫厤鐤€冮€告満鍒讹紙濡侾D-1-PD-L1绛夛級鐨勶紝杩欐槸涓€鏉″叏鏂扮殑鍏嶇柅閫冮€告満鍒�銆�

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

闃绘柇FGL1- LAG-3閫氳矾鍙互鎶戝埗鑲跨槫

褰撶劧锛屼互涓婂疄楠岄兘鏄湪灏忛紶浣撳唴杩涜鐨勶紝閭ｅ湪浜轰綋鍐呮槸鍚︿篃濡傛鍛紵

鍏跺疄姝ｅ父鎯呭喌涓嬶紝FGL1铔嬬櫧鐨勮〃杈炬槸琚眬闄愪簬姝ｅ父鐨勮倽鑴忓拰鑳拌吅缁勭粐涓€�

浣嗘槸褰撶爺绌朵汉鍛樻煡璇㈣偪鐦ょ浉鍏崇殑鏁版嵁搴撴椂锛�鍗村彂鐜板緢澶氬疄浣撶槫涓紝鍖呮嫭鑲虹檶銆佸墠鍒楄吅鐧屻€侀粦绱犵槫銆佺粨鑲犵洿鑲犵檶浠ュ強涔宠吅鐧岋紝閮藉嚭鐜拌〃杈炬槑鏄句笂璋冪殑鐜拌薄锛岃€屽湪鑲虹檶涓殑姣斾緥鏈€楂樸€�

闅忓悗锛屼粬浠篃閫氳繃瀹為獙璇佸疄鍦ㄥ緢澶氫汉绫昏偪鐦ょ粍缁囦腑锛孎GL1铔嬬櫧鐨勮〃杈剧‘瀹炴槸涓婅皟鐨勶紝灏ゅ叾鏄潪灏忕粏鑳炶偤鐧屻€�

鏃㈢劧FGL1- LAG-3鍏嶇柅鎶戝埗閫氳矾鏄嫭绔嬩簬PD-1-PD-L1閫氳矾鐨勶紝杩欐殫绀哄湪FGL1- LAG-3琚縺娲荤殑鑲跨槫涓紝浠呬粎鎶戝埗PD-1-PD-L1閫氳矾鍙兘鏄笉澶熺殑銆�

浜嬪疄涓婏紝褰撶爺绌惰€呮娴嬩簡鎺ュ彈PD-(L)1鎶戝埗鍓傛不鐤楃殑鎮ｈ€咃紙鍖呮嫭闈炲皬缁嗚優鑲虹檶鍜岄粦鑹茬礌鐦わ級琛€娓呬腑FGL1铔嬬櫧鐨勫惈閲忔椂锛� 鍙戠幇FGL1铔嬬櫧姘村钩楂樼殑鎮ｈ€呮不鐤楁晥鏋滄洿宸紝鐢熷瓨鏈熸洿鐭�銆傝繖琛ㄦ槑FGL1铔嬬櫧姘村钩鎴栬鍙互浣滀负棰勬祴PD-(L)1鎶戝埗鍓傛不鐤楁晥鏋滅殑鐢熺墿鏍囧織鐗┿€�

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

FGL1铔嬬櫧姘村钩楂樼殑鎮ｈ€呭厤鐤不鐤楁晥鏋滄洿宸�

鏇撮噸瑕佺殑鍦ㄤ簬杩欏彲鑳介绀虹潃涓€绉嶆柊鐨勬姉鐧岀瓥鐣ャ€傚皢杩欎袱鏉￠€氳矾鍚屾椂鎶戝埗锛屾垨璁稿彲浠ュ讥琛D-(L)1鎶戝埗鍓傛不鐤楁晥鏋滀笉浣崇殑缂洪櫡銆�

鍦ㄥ皬榧犱腑鐨勫疄楠岃瘉鏄庝簡杩欎竴鐐广€�

褰撶爺绌朵汉鍛樺皢鑲跨槫灏忛紶鐨勮繖涓ゆ潯閫氳矾鍚屾椂鎶戝埗鏃讹紝鍙戠幇娌荤枟鏁堟灉瑕佹槑鏄惧ソ浜庡彧鎶戝埗鍏朵腑涓€鏉°€�鑱斿悎娌荤枟鐨勫皬榧犵敓瀛樻湡鏇撮暱锛岃偪鐦よ礋鑽锋洿灏�銆�

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

鑱斿悎娌荤枟鐨勬晥鏋滄槸鏈€濂界殑

褰撶劧锛屽湪浜轰綋涓殑鏁堟灉杩樻槸瑕佺湅鏈€缁堜复搴婅瘯楠岀殑缁撴灉銆備絾鏄粠鐜版湁鐨勮瘉鎹湅锛屾綔鍔涙槸闈炲父澶х殑锛岃繖涔熻鎴戜滑鍏呮弧鏈熷緟銆�

闄堝垪骞虫暀鎺堝湪杩欎釜鍙戠幇涓哄厤鐤枟娉曡ˉ鍏呬竴鍧楅噸瑕佺殑鎷煎浘锛�鎴栬鍙互瑙ｅ喅鐜板湪PD-(L)1鎶戝埗鍓傜枟鏁堜笉瓒崇殑闂锛屼娇寰楀厤鐤不鐤楁洿鍔犲畬鍠勶紝璁╂洿澶氱殑鎮ｈ€呭彈鐩�锛�

缂栬緫绁炲彣鍙�

璇濊鍏嶇柅绯荤粺鐨勫埞杞﹁繕鐪熷鍟婏紝鑰佽鍧忚泲涔辫俯銆備笉杩囨€荤畻鍙戠幇浜嗛殣鎮ｏ紝鍫典綇缂哄彛锛岃偪鐦ゆ槸涓嶆槸鎻掔繀闅鹃€冧簡鍛紵鎯充簡瑙ｆ渶鏂板尰瀛︾殑杩涘睍鍚楋紵閮藉湪杩欎釜灏忕▼搴忛噷~

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

鍙傝€冩枃鐚細

[1] Jun Wang et al., (2018), Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3, Cell, DOI:10.1016/j.cell.2018.11.010

[2]http://m.zhishifenzi.com/depth/depth/3132.html

[3] Andrews, L.P., Marciscano, A.E., Drake, C.G., and Vignali, D.A. (2017). LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80鈥�96

[4] Yao, S., Zhu, Y., Zhu, G., Augustine, M., Zheng, L., Goode, D.J., Broadwater, M., Ruff, W., Flies, S., Xu, H., et al. (2011). B7-h2 is a costimulatory ligand for CD28 in human. Immunity 34, 729鈥�740

[5] Yamamoto, T., Gotoh, M., Sasaki, H., Terada, M., Kitajima, M., and Hirohashi, S. (1993). Molecular cloning and initial characterization of a novel fibrinogenrelated gene, HFREP-1. Biochem. Biophys. Res. Commun. 193, 681鈥�687

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

銆婄粏鑳炪€嬮噸纾咃細鍘夊浜嗛檲鍒楀钩鏁欐巿锛侀檲鍒楀钩鍥㈤槦鍙戠幇涓€鏉″叏鏂拌偪鐦ゅ厤鐤姂鍒堕€氳矾锛屽厤鐤不鐤楅鍩熻繋鏉ュ張涓€閲嶇闈剁偣涓ㄧ瀛﹀ぇ鍙戠幇

鏈枃浣滆€� | 浣庢俯鑹烘湳瀹�