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腫瘤分化誘導(dǎo)劑綠原酸抑制PD-L1表達,增強PD-1抗體的免疫,發(fā)揮抗腫瘤作用
[ 來源:Int. J. Biol. Sci. 2024 Jan 1;20(1):61-77.   發(fā)布日期:2024-07-09 13:22:14  責(zé)任編輯:  瀏覽次 ]

1. 中國醫(yī)學(xué)科學(xué)院、北京協(xié)和醫(yī)學(xué)院,醫(yī)藥生物技術(shù)研究所,北京,100050

2. 中國醫(yī)學(xué)科學(xué)院、北京協(xié)和醫(yī)學(xué)院,藥物研究所、天然藥物生物活性物質(zhì)與功能國家重點實驗室,北京,100050

3. 中國科學(xué)院昆明植物研究所,植物化學(xué)與西部植物資源持續(xù)利用國家重點實驗室,云南昆明,650201

4. 九章生物科技發(fā)展有限公司,四川成都,610041

5. 首都醫(yī)科大學(xué)附屬北京天壇醫(yī)院腫瘤中心,神經(jīng)腫瘤科,北京,100070

摘要: 由于免疫檢查點抑制劑已顯示出良好的臨床療效,免疫檢查點阻斷已經(jīng)成為癌癥治療的重要策略。然而,大約只有12.5%的患者受益于免疫療法。在此,我們提出了一種癌癥分化誘導(dǎo)劑綠原酸(chlorogenic acid, CGA,目前正處于中國治療膠質(zhì)瘤的II期臨床試驗中),它是一種小分子免疫檢查點抑制劑,可以增強PD-1抗體的免疫,發(fā)揮抗腫瘤作用。CGA通過抑制p-STAT1-IRF1通路和增強活化T細胞的活性,可以抑制干擾素誘導(dǎo)的PD-L1在腫瘤細胞中的表達。在CGA與抗PD -1抗體聯(lián)合治療小鼠腫瘤異種移植中,可降低腫瘤細胞凋亡,抑制PD-L1IRF1的表達,增強了抗PD-1抗體對細胞的抑制作用,抑制腫瘤的生長。特別是,CGA可增強腫瘤浸潤T細胞的活性。改善腫瘤浸潤免疫細胞顆粒酶基因表達。總之,通過誘導(dǎo)分化,CGA抑制了PD-L1在癌癥細胞中的表達,有效促進腫瘤中浸潤的T細胞,增強抗腫瘤作用。因此,CGA如果與抗PD -1抗體聯(lián)合使用,可能是一種很有前景的增強抗癌作用的藥物免疫療法。

 

關(guān)鍵詞:綠原酸,腫瘤分化誘導(dǎo)劑,PD-L1,抗PD -1抗體,聯(lián)合治療

1簡介

免疫檢查點是一種避免自身免疫反應(yīng),保持免疫系統(tǒng)處于穩(wěn)態(tài)的重要機制。然而,激活免疫檢查點也是腫瘤患者帶瘤生存主要的途徑之一。檢查點通路的啟動導(dǎo)致細胞毒性T淋巴細胞的衰竭,隨后使腫瘤細胞繞過免疫監(jiān)視。PD-1/PD-L1軸是眾所周知的免疫途徑檢查點其中之一。PD-L1已在黑色素瘤,肺癌,乳腺癌、卵巢癌、胰腺癌和結(jié)腸癌等進行研究。作為一個免疫檢查點分子,PD-L1的功能是與其受體PD-1相互作用,PD-1在腫瘤浸潤性T淋巴細胞表面表達,引起細胞毒性T細胞活化的抑制,繞過對癌癥的免疫監(jiān)控。在過去的幾十年里,抗體對抗免疫檢查點分子已成為一個研究熱點,試圖發(fā)現(xiàn)癌癥藥物的免疫療法。

第一個免疫檢查點抑制劑(ICI)是伊匹單抗,是一種細胞毒 T 淋巴細胞相關(guān)抗原4 (CTLA-4),臨床有效治療轉(zhuǎn)移性黑色素瘤。隨后,PD-1抗體(派姆單抗和納武利尤單抗)及其配體PD-L1 (阿替利珠單抗,德瓦魯單抗和阿維魯單抗)已經(jīng)被批準(zhǔn),并被廣泛用于治療不同類型的癌癥。此外,新型ICIs的臨床試驗也在進行,世界各地的醫(yī)院都在對癌癥進行檢測。然而,盡管取得了巨大的成功,預(yù)期抗癌免疫反應(yīng)僅見于12.5%的部分患者。觀察患者的免疫反應(yīng),抗癌的區(qū)別歸因于各種原因,如PD-L1PD-1的表達水平,基因突變細胞,以及新抗原的發(fā)展,這是對癌癥免疫療法的巨大挑戰(zhàn)。

為避免患者使用ICIs無效,生物標(biāo)志物的研究是目前的方法之一。聯(lián)合ICI抗體與常規(guī)抗癌藥物是促進治療效果的又一嘗試。如聯(lián)合抗pd -1抗體和吉西他濱通過激活巨噬細胞和CD8+ T細胞,增強了抗體的抗癌作用。盡管PD-1單藥治療抑制劑或它們的聯(lián)合療法臨床取得顯著效果,對PD-1抑制劑的應(yīng)答率低仍然是一個大問題。因此,基于機制的理性設(shè)計對于優(yōu)化ICIs治療是非常可取的。

誘導(dǎo)腫瘤分化是我們的新課題,將癌細胞從高侵入性和轉(zhuǎn)移表型轉(zhuǎn)變?yōu)閻盒猿潭容^低或接近正常狀態(tài)。根據(jù)生物學(xué)原理,PD-L1在癌細胞中的表達與腫瘤惡性相關(guān),應(yīng)該是陽性的,就像成功創(chuàng)造了一種免疫逃逸機制。最近研究表明出現(xiàn)了PD-L1表達與癌細胞或/和干細胞分化不良有關(guān)。孫等人指出指出,間充質(zhì)干細胞(MSCs)可通過STAT3/mTORc-Myc通路 誘導(dǎo)PD-L1在胃癌細胞中的表達。同時也有人證明了這一點,證明了這一點,在非小細胞肺癌中,PD-L1介導(dǎo)的免疫逃逸與c-MycEGFR/MAPK信號有關(guān)。也有人證明了c-Myc可以誘導(dǎo)PD-L1在食管鱗狀細胞癌中的表達,而其他研究顯示PD-L1可能會增強肺腺癌中c-Myc的活性。這些發(fā)現(xiàn)提出了癌癥治療中的腫瘤分化與誘導(dǎo)的免疫檢查點。因此,我們假設(shè)一種改善的分化狀態(tài)使腫瘤細胞中PD-L1的產(chǎn)生減少,從而增強腫瘤細胞毒性t細胞的活性微環(huán)境。如果成立,癌癥分化誘導(dǎo)劑除了它們自身的抗癌作用,還可促進ICIs的抗癌活性。

綠原酸(CGA),是一種多酚化合物,可作為消炎藥使用,據(jù)報道,綠原酸具有多種藥理活性,如抗氧化、抗炎、保護神經(jīng)。最近的研究表明,CGA能抑制各種癌癥細胞的增殖。九章生物的I期臨床試驗(肌內(nèi)注射)顯示CGA耐受性很好,在復(fù)發(fā)性高級別膠質(zhì)瘤患者中,獲益性良好。基于此研究結(jié)果,中國FDA已于2017年批準(zhǔn)CGA進行復(fù)發(fā)性高級別膠質(zhì)瘤患者的II期臨床試驗(NCT2013 L01855)。對于它的作用機理,以前的研究工作已經(jīng)證明CGA通過誘導(dǎo)癌細胞分化,抑制癌和肺癌的腫瘤生長。與低分化相關(guān)的基因的表達,如c-Myc,主要由CGA,通過上調(diào)SUMO1的表達和c-Myc;,導(dǎo)致癌細胞中c-Myc的強烈抑制和向成熟表型的轉(zhuǎn)化。同時,我們也發(fā)現(xiàn)了CGA在劑量和時間依賴性的食管鱗狀細胞癌中,能夠下調(diào)腫瘤相關(guān)的干細胞標(biāo)記物BMI1SOX2的表達。在本研究中, CGA誘導(dǎo)腫瘤分化,可以下調(diào)腫瘤PD-L1表達,激活腫瘤組織中的細胞毒性T淋巴細胞,并可與目前可用的ICI抗體聯(lián)合使用。由于CGA對人體是安全的,所以此研究可能很快就會轉(zhuǎn)化為臨床使用。

2 結(jié)論

用抗體阻斷PD-1/PD-L1相互作用的免疫療法在癌癥治療應(yīng)用已經(jīng)取得了很大的成功。然而,免疫反應(yīng)在患者的情況各不相同,大多數(shù)患者未能從中受益。PD-L1在腫瘤組織中的表達被認為是一種機制,甚至是至關(guān)重要的生物標(biāo)志物,能夠預(yù)測腫瘤患者的抗癌免疫反應(yīng)。PD-L1表達下調(diào)可能會增強抗癌作用,發(fā)揮免疫治療。在本研究中,我們發(fā)現(xiàn)腫瘤分化誘導(dǎo)劑CGA可以降低癌細胞中PD-L1的表達,從而保護腫瘤浸潤的T細胞免受PD-1/PD-L1的攻擊,導(dǎo)致T細胞死亡等,增強PD -1抗體的治療效果。因此,CGA作為免疫檢查點抑制劑,聯(lián)合抗PD -1抗體可能是一種提高療效的新方法。

癌細胞分化代表了程序化細胞內(nèi)協(xié)同過程,將癌細胞從惡性轉(zhuǎn)移到良性或正常細胞,以減少增殖和轉(zhuǎn)移為特征,發(fā)揮免疫檢查點功能。這個生物過程是復(fù)雜的,并且在觸發(fā)程序信號之后,癌細胞的通路和基因表達基本都受到了監(jiān)管。由CGA重新編程,減少PD-L1表達可能是一個重要的癌細胞分化的跡象和途徑,至少涉及IFN-γ/JAK/pSTAT1/IRF1/PD-L1

IFN-γ,由細胞毒性T細胞和天然殺傷細胞分泌,是先天或適應(yīng)性免疫反應(yīng)重要分子。就像一把雙刃劍,IFN-γ不僅參與細胞毒性,同時還能誘導(dǎo)細胞中PD-L1的表達,最終導(dǎo)致腫瘤免疫逃避。在本研究中,我們發(fā)現(xiàn)CGA在黑色素瘤癌細胞,三陰性乳腺癌細胞和卵巢癌細胞中,抑制IFN-γ誘導(dǎo)的人PD-L1表達黑色素瘤癌細胞,三陰性乳腺癌細胞和卵巢癌細胞。mRNA影響蛋白表達的穩(wěn)定性,我們首先檢測PD-L1 mRNA的穩(wěn)定性,發(fā)現(xiàn)它沒有被CGA處理破壞。然后,檢測PD-L1啟動子(表達PD-L1的另一個重要因素)的活性。我們發(fā)現(xiàn)PD-L1啟動子的活性被CGA抑制。JAK-pSTAT1-IRF1通路是與IFN-γ誘導(dǎo)的,以及通路上游的IFN-γ結(jié)合IFN-γ受體(IFNGR1IFNGR2),

然后激活JAK-pSTAT1-IRF1通路。作為一種轉(zhuǎn)錄因子,IRF1與啟動子序列,從而激活PD-L1基因表達。我們首先測試了表達的IFNGR1IFNGR2,之后沒有發(fā)現(xiàn)CGA的變化。然而,過度表達轉(zhuǎn)錄因子IRF1消除了CGAPD-L1啟動子活性這種抑制作用;

表明IRF1CGA活性的主要機制。先前的研究表明STAT1是在IFN-γIRF1激活之前被磷酸化誘導(dǎo)的PD-L1刺激通路。本研究中,我們發(fā)現(xiàn)CGA下調(diào)了STAT1的磷酸化,與以前的報告一致。因此,CGA可能通過抑制STAT1磷酸化- IRF1 - PD-L1通路,抑制PD-L1在腫瘤細胞中的表達。此外,據(jù)報道,IRF1可以結(jié)合STAT1DNA并促使STAT1的磷酸化, CGA下調(diào)IRF1可以進一步減弱STAT1磷酸化和增強對PD-L1的抑制作用。同時,p-STAT1是一種直接結(jié)合PD-L1啟動子的轉(zhuǎn)錄因子; CGA的磷酸化從而抑制STAT1,抑制PD-L1的表達。事實上, CGA的增加,在腫瘤/免疫細胞共培養(yǎng)系統(tǒng),使A375MDA-MB-231SK-OV-3的易感性細胞向活化的Jurkat E6細胞轉(zhuǎn)移。這些結(jié)果表明CGA對腫瘤細胞PD-L1表達的抑制作用可以增加T細胞的活性,使阻斷腫瘤免疫檢查點功能。

簡而言之,通過聯(lián)合治療PD-L1IRF1的表達在腫瘤組織中顯著減少,以及藥物相互作用阻斷了PD-1PD-L1之間的聯(lián)系,因此T細胞介導(dǎo)的抗腫瘤免疫療法得到了推廣。在體外實驗,延長CGA處理時間,增強腫瘤細胞中PD-L1表達的抑制作用,表明在細胞分化的進展抑制作用增強了。

腫瘤對免疫療法的反應(yīng)從高到無。因此,它們被分為“Hot”、“ Cold”“Altered”,該定義與腫瘤組織浸潤的T細胞數(shù)量有關(guān)。高T細胞浸潤的癌癥在腫瘤微環(huán)境中被認為是“Hot”,低滲區(qū)為“Cold”區(qū),腫瘤浸潤邊緣有T細胞浸潤和/或顯示低CD8+免疫抑制亞型屬于“Altered”組。本研究選取兩種異種移植物模型小鼠MC38作為“Hot”腫瘤模型,4T1“Altered”模型,根據(jù)抗pd -1抗體及浸潤水平CD8+ T細胞的腫瘤免疫反應(yīng)(圖1、2)。檢測到CGA與抗pd -1抗體結(jié)合;結(jié)果表明CGA聯(lián)合抗pd -1抗體治療效果較好,效果優(yōu)于單一療法,無論是“Hot” 還是“Altered” 異種移植模型,均腫瘤生長產(chǎn)生額外抑制作用 (治療效果31.1%, MC38升高,p < 0.05;治療效果24.5%,4T1升高,p < 0.01)。

 


1   CGA在體內(nèi)增強了抗pd -1抗體的抗腫瘤作用。

a e.CGA提高了小鼠結(jié)腸癌抗PD-1抗體的抗腫瘤作用。在C57BL/6N雄性小鼠背部皮下注射2 × 105個小鼠結(jié)腸癌MC38細胞。接種3天后,隨機分組分為生理鹽水聯(lián)合IgG:NS + IgG組,生理鹽水聯(lián)合抗PD-1抗體組:NS +pd -1抗體組,CGA聯(lián)合IgG:CGA + IgG組,CGA聯(lián)合抗PD-1抗體:CGA +pd -1) (n = 7)。CGA (50 mg / kg)每天1(i.p),連續(xù)3周分別于第3、710天給予抗體200 ug。A.荷瘤小鼠的代表圖像。腫瘤用紅色圈出。B.代表切除腫瘤的圖像。C.腫瘤生長示意圖。D.各組小鼠腫瘤重量比較。E.體重的變化。F-J. CGA提高了抗PD-1抗體對小鼠乳腺癌的抗腫瘤作用。將1 × 105個小鼠乳腺癌細胞4T1注射到BALB / c雌性小鼠乳腺脂肪中。接種3天后,將小鼠隨機分為上述4組。CGA (50 mg / kg)每日1(ig),連用19例連續(xù)第3天,第7天,第10天分別給予200 ug抗體。F.荷瘤小鼠代表像。腫瘤被圈起來紅色的。G.切除腫瘤的代表圖像。H.腫瘤生長示意圖。1 .各組小鼠腫瘤重量比較。所示數(shù)據(jù)為平均值±SD。經(jīng)單因素方差分析,與NS + IgG組比較,*p< 0.05 **p< 0.01, **p< 0.001。NS表示生理鹽水;免疫球蛋白。

 

2 CGA可促進腫瘤組織中細胞毒性T淋巴細胞的浸潤。

從新鮮腫瘤組織中分離細胞毒性T淋巴細胞(CTLs)解離成單細胞懸液,流式細胞術(shù)分析。Aa. 浸潤細胞毒性T細胞(CD8+ CD3+)的代表性流式細胞儀圖譜。Ab. 浸潤的細胞毒性T細胞百分比。Ba.浸潤效應(yīng)T細胞(IFN-γ+ CD8+ CD3+)的代表性流式細胞儀圖譜。Bb. 滲透效應(yīng)T細胞百分比。C.腫瘤組織CD8(粉色)IFN-γ(紅色)染色的代表性多色免疫熒光圖像。10μm。Da.代表性流式細胞儀4T1荷瘤小鼠腫瘤組織中浸潤Treg細胞(Foxp3+ CD25+ CD4+)的譜圖。Db.浸潤Treg細胞百分比。數(shù)據(jù)以mean±SD表示(n = 5)。與NS + IgG比較,*p< 0.05, **p< 0.01 **p< 0.001。組采用單因素方差分析檢驗。

這種聯(lián)合用藥對腫瘤生長的抑制作用MC38(“Hot”)4T1(“Altered”)更顯著。對這種差異的解釋可能是相關(guān)的T細胞定位于腫瘤組織,其中浸潤T細胞的數(shù)量、細胞類型和活性會影響小鼠的抗腫瘤免疫微環(huán)境?偟膩碚f,在Hot模型中,T細胞數(shù)量和活性較高。因此,在AlteredCold模型中,需產(chǎn)生強烈的免疫反應(yīng)來對抗癌癥。在本研究中,浸潤T兩種腫瘤組織中CD3+ CD8+的表達 (2A-B)可能有助于獨特的腫瘤抑制。

細胞毒性T淋巴細胞(CTLs) 在抗腫瘤免疫是主要的免疫細胞。IFN-γ+ CD8+ T在腫瘤細胞毒性中發(fā)揮重要作用,因此這個T細胞亞群的比例是抗腫瘤免疫陽性指標(biāo)。在研究CGACTLs的影響,我們發(fā)現(xiàn)CD8+ CD3+ T細胞群(CTLs的子集),在聯(lián)合組和CGA或抗pd -1抗體單藥治療組中均增強。隨后我們分析IFN-γ+腫瘤組織在CD8+ T細胞中的浸潤比例。數(shù)據(jù)顯示,在兩種小鼠腫瘤模型中,聯(lián)合用藥組IFN-γ+ CD8+ T細胞比例增高;MC38荷瘤小鼠中IFN-γ+ CD8+ T細胞的增加更為明顯明顯優(yōu)于單藥治療(2B;2.77倍相對于NS + Anti-PD-L1上調(diào)組,p < 0.001),相同的結(jié)果見圖1A-D。這些結(jié)果表明CGA可以增加腫瘤微環(huán)境中的細胞毒性T細胞。同時,調(diào)節(jié)性T細胞(Treg),在抗腫瘤免疫治療中的一種抑制因子,與癌癥預(yù)后不良相關(guān)?pd -1單藥治療抗體增加腫瘤組織中Treg細胞的數(shù)量,然而,這種不希望的增長在CGA4T1腫瘤模型聯(lián)合治療中被逆轉(zhuǎn)了 (2D)?贵w單藥治療中Treg細胞的增加,有可能使PD-1表達的Treg細胞受到抗pd -1的保護,抗體通過阻斷PD-1之間的相互作用抑制腫瘤組織中PD-L1的表達;但CGA聯(lián)合給藥組對Treg細胞的影響需要更多的研究。實驗中發(fā)現(xiàn),CGA并沒有改變?nèi)?/span>T細胞免疫動物應(yīng)答,但可能有效調(diào)節(jié)巨噬細胞細胞因子。

顆粒酶是CTLs和殺傷細胞分泌的一組蛋白酶,在穿孔素的幫助下執(zhí)行細胞殺傷作用。顆粒酶B (Granzyme B, GZMB)是蛋白質(zhì)的主要分子之一,據(jù)報道,顆粒酶家族在PD-1封閉療法治療后,與臨床結(jié)果呈正相關(guān)。在研究中發(fā)現(xiàn),與抗PD -1單藥治療相比聯(lián)合治療中瘤顆粒酶基因上調(diào), (3)在兩種模型腫瘤蛋白組織水平上進一步得到驗證。我們認為這有益于腫瘤微環(huán)境增強T細胞激活和/T細胞計數(shù)。

 


3. CGA上調(diào)腫瘤組織中顆粒酶B (GZMB)的表達。

PD -1抗體單藥治療組(NS+pd -1, n =3)收集4T1荷瘤小鼠的CGA+PD-1抗體聯(lián)合治療組(CGA+pd -1, n = 3)。腫瘤組織總RNA采用“l(fā)imma”“DESeq”R包進行RNA序列分析。差異表達基因(DEGs)富集氧化石墨烯的功能。A. DEGs火山圖,log2FC|≥1,p≤0.05。B. GO生物過程功能項富集前20名。C. NS+Anti-PD-1CGA+Anti-PD-1組細胞溶解功能基因表達熱圖?潭缺硎緦(shù)變換后的TPMs + 1,紅到藍表示相對基因表達由高到低。實驗組中,NS+Anti-PD-1-1、NS+Anti-PD-1-2、NS+Anti-PD-1-3、CGA+Anti-PD-1-1CGA+Anti-PD-1-2、CGA+Anti-PD-1-3為測序樣品。D~ECGA+PD-1治療可上調(diào)腫瘤組織中GZMB蛋白的表達。腫瘤組織中CD8(粉色)GZMB(綠色)染色的彩色免疫熒光圖像(D)10μm。Western blot檢測GZMB蛋白表達分析(E). GZMB結(jié)果歸一化為β-肌動蛋白密度比。數(shù)據(jù)以mean±SD表示(n = 6),差異有統(tǒng)計學(xué)意義:*p< 0.05, **p< 0.01,與NS+Anti-PD-1組進行學(xué)生t檢驗。GZMB表示顆粒酶B

總之,CGA是一種已知的癌癥分化誘導(dǎo)劑(CDI),在中國,CGA治療神經(jīng)膠質(zhì)瘤的臨床試驗已進入II期臨床后期階段。CGA通過抑制IFN-γ誘導(dǎo)的干擾素-γ/ JAK / pSTAT1 / IRF1 / PD-L1通路抑制腫瘤細胞中的PD-L1。因此,CGA是一種安全的免疫增強劑,增強腫瘤中T細胞的活性微環(huán)境,與抗pd -1抗體聯(lián)合使用時可提高抗癌效果(4)。

4  CGA通過抑制STAT1磷酸化和抑制IFN-γ誘導(dǎo)的PD-L1表達,發(fā)揮腫瘤免疫治療作用

致謝

   該項目得到了CAMS醫(yī)學(xué)科學(xué)創(chuàng)新基金(No.2022-I2M-2-002, 2022-I2M-JB-012) 的支持;中國科學(xué)院植物化學(xué)與植物重點實驗室與中國西部資源國家基金(No. P2022-KF01)。

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36. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002; 2: 735-47.

37. Cerezo M, Guemiri R, Druillennec S, Girault I, Malka-Mahieu H, Shen S, et al. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat Med. 2018; 24: 1877-86.

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41. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. SCIENCE. 2016; 352: 227-31.

42. Zenke K, Muroi M, Tanamoto KI. IRF1 supports DNA binding of STAT1 by promoting its phosphorylation. Immunol Cell Biol. 2018; 96: 1095-103.

43. Nakayama Y, Mimura K, Tamaki T, Shiraishi K, Kua LF, Koh V, et al. PhosphoSTAT1 expression as a potential biomarker for antiPD1/antiPDL1 immunotherapy for breast cancer. Int J Oncol. 2019; 54: 2030-8.

44. Xu L, Zhang Y, Tian K, Chen X, Zhang R, Mu X, et al. Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects. J Exp Clin Cancer Res. 2018; 37: 261-76.

45. Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. 2018; 6: 157.

46. Bonaventura P, Shekarian T, Alcazer V, Valladeau-Guilemond J, Valsesia-Wittmann S, Amigorena S, et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy. Front Immunol. 2019; 10: 168.

47. Grasselly C, Denis M, Bourguignon A, Talhi N, Mathe D, Tourette A, et al. The Antitumor Activity of Combinations of Cytotoxic Chemotherapy and Immune Checkpoint Inhibitors Is Model-Dependent. Front Immunol. 2018; 9: 2100-13.

48. Thommen DS, Schumacher TN. T Cell Dysfunction in Cancer. Cancer Cell. 2018; 33: 547-62.

49. Hossain MA, Liu G, Dai B, Si Y, Yang Q, Wazir J, et al. Reinvigorating exhausted CD8(+) cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy. Med Res Rev. 2021; 41: 156-201.

50. Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics. 2021; 11: 5365-86.

51. St Paul M, Ohashi PS. The Roles of CD8(+) T Cell Subsets in Antitumor Immunity. Trends Cell Biol. 2020; 30: 695-704.

52. Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, et al. PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A. 2019; 116: 9999-10008.

53. Zhang Y, Yang Y, Ye J, Gao Y, Liao H, Zhou J, et al. Construction of chlorogenic acid-containing liposomes with prolonged antitumor immunity based on T cell regulation. Sci China Life Sci. 2021; 64: 1097-115.

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