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人才隊(duì)伍

許琛琦
研究員，研究組長，博士生導(dǎo)師，所長助理
E-mail: cqxu@@sibcb.ac.cn
實(shí)驗(yàn)室主頁: http://xulab.sibcb.ac.cn

個(gè)人簡介：

　　2004年畢業(yè)于中科院生物化學(xué)與細(xì)胞生物學(xué)研究所，獲理學(xué)博士學(xué)位。2004年赴美國哈佛大學(xué)醫(yī)學(xué)院Dana-Farber腫瘤研究所從事免疫學(xué)研究，先后為博士后(受美國關(guān)節(jié)炎基金會資助)，instructor。2009年11月回生化與細(xì)胞所工作，擔(dān)任研究員與研究組長，現(xiàn)任所長助理、分子生物學(xué)國家重點(diǎn)實(shí)驗(yàn)室副主任、中國生物化學(xué)與分子生物學(xué)會副秘書長。先后入選國家杰出青年基金、科技部中青年科技創(chuàng)新領(lǐng)軍人才、上海市科委優(yōu)秀學(xué)術(shù)帶頭人計(jì)劃;成果入選中國科學(xué)十大進(jìn)展和中國生命科學(xué)十大進(jìn)展;獲談家楨生命科學(xué)獎(jiǎng)創(chuàng)新獎(jiǎng)、中源協(xié)和生命醫(yī)學(xué)獎(jiǎng)、全國優(yōu)秀科技工作者、上海青年科技英才等獎(jiǎng)項(xiàng)。

社會任職：

研究方向：

淋巴細(xì)胞與疾病

研究工作：

　　免疫系統(tǒng)是機(jī)體執(zhí)行免疫應(yīng)答及免疫功能的重要系統(tǒng)，它能夠區(qū)分“自身”和“非自身”，并通過清除“非自身物質(zhì)”來保護(hù)機(jī)體。免疫系統(tǒng)可以分為固有免疫和適應(yīng)性免疫。固有免疫系統(tǒng)在低等動(dòng)物中就開始出現(xiàn)，可以識別病原體所攜帶的特殊模式以及體內(nèi)的危險(xiǎn)信號，從而迅速地做出免疫反應(yīng)。適應(yīng)性免疫系統(tǒng)是高等動(dòng)物逐漸進(jìn)化出的特殊功能系統(tǒng)，最大的特點(diǎn)是能夠針對不同的抗原做出高度特異性和靈敏性的免疫反應(yīng)。T淋巴細(xì)胞(簡稱T細(xì)胞)是適應(yīng)性免疫系統(tǒng)的主要功能細(xì)胞，在清除病原體和腫瘤細(xì)胞過程中發(fā)揮著至關(guān)重要的作用。T細(xì)胞的活性異常與腫瘤、自身免疫病等多種重大疾病直接相關(guān)。基于T細(xì)胞功能調(diào)控的腫瘤免疫治療已成為治療腫瘤的主要武器之一，在臨床上已取得了巨大的成功。但現(xiàn)有的基于信號轉(zhuǎn)導(dǎo)調(diào)控的腫瘤免疫治療手段只對部分病人有效，因此急需發(fā)展新的方法讓更多的病人受益。本研究組交叉利用免疫學(xué)、生物化學(xué)、生物物理學(xué)前沿手段，著力于T細(xì)胞活性調(diào)控的分子機(jī)制研究，揭示了T細(xì)胞發(fā)揮免疫功能的分子基礎(chǔ)，并且發(fā)展了新的腫瘤免疫治療方法。
　　1. 抗原免疫應(yīng)答的調(diào)控機(jī)制
　　抗原免疫應(yīng)答過程涉及多種免疫受體的協(xié)同作用。本課題組對抗原受體TCR，共刺激受體CD28和共抑制受體PD-1的活化機(jī)制做了深入而系統(tǒng)的研究，我們創(chuàng)新性地提出了“膜脂調(diào)控”理論，指出酸性磷脂可以通過靜電相互作用調(diào)控免疫受體的活化過程。
　　T細(xì)胞的活化主要依賴于抗原受體TCR(T-cell receptor)和共刺激受體CD28。我們的前期研究表明TCR的活性受酸性磷脂調(diào)控。帶負(fù)電的酸性磷脂可以和帶正電的TCR胞內(nèi)區(qū)動(dòng)態(tài)結(jié)合，從而將TCR的磷酸化位點(diǎn)屏蔽在膜內(nèi)，保證TCR在靜息態(tài)T細(xì)胞中處于功能關(guān)閉狀態(tài)(Cell 2008)。我們隨后發(fā)現(xiàn)TCR初始信號引發(fā)的鈣離子內(nèi)流能夠反饋調(diào)控TCR。Ca2+可以直接結(jié)合酸性磷脂的磷酸根，中和其攜帶的負(fù)電荷，從而打破TCR與酸性磷脂之間的靜電相互作用，促進(jìn)TCR功能位點(diǎn)的解屏蔽及磷酸化，從而放大TCR的活化信號(Nature 2013)。這一新的分子機(jī)制突破了以往對Ca2+功能的傳統(tǒng)認(rèn)識。在這項(xiàng)工作基礎(chǔ)上，我們進(jìn)一步發(fā)現(xiàn)Ca2+的正反饋調(diào)控還適用于CD28。酸性磷脂同樣可以屏蔽CD28的磷酸化位點(diǎn)，而Ca2+也能夠通過中和酸性磷脂負(fù)電荷的機(jī)制來放大CD28信號(Nature Structural & Molecular Biology 2017)。我們由此提出TCR，Ca2+，CD28這三者之間組成了一個(gè)雙環(huán)路的正反饋網(wǎng)絡(luò)，可以將微弱的初始抗原刺激信號迅速放大，使T細(xì)胞獲得完全的效應(yīng)功能，從而為T細(xì)胞高靈敏性提供了信號基礎(chǔ)(圖1)。“膜脂調(diào)控”理論在我們的合作研究中同樣被證明適用于多種免疫受體，比如鈣離子在記憶型B細(xì)胞的迅速活化過程中也起到關(guān)鍵的作用(Nature Communications 2015，The Journal of Physical Chemistry Letters, 2017)。我們也撰寫了多篇綜述來闡述這個(gè)學(xué)術(shù)思想(Trends Biochem Sci 2014, Trends Immunol 2016, Nat Rev Immunol 2016)。
　　圖1. TCR-Ca2+-CD28雙環(huán)路正反饋模型。T細(xì)胞活化主要依賴TCR和CD28。這兩個(gè)關(guān)鍵受體的磷酸化位點(diǎn)都被酸性磷脂通過靜電效應(yīng)屏蔽，而Ca2+可以通過中和酸性磷脂負(fù)電荷的形式釋放受體磷酸化位點(diǎn)，促進(jìn)受體活化。TCR和CD28的活化都能夠誘導(dǎo)Ca2+內(nèi)流。TCR-Ca2+-CD28這三者之間由此形成雙環(huán)路的正反饋網(wǎng)絡(luò)，可以將微弱的初始刺激信號迅速放大，為T細(xì)胞的高抗原敏感性提供信號基礎(chǔ)。
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　　我們還發(fā)現(xiàn)TCR的結(jié)構(gòu)多態(tài)性和酪氨酸激酶Lck的底物選擇性是T細(xì)胞高特異性的分子基礎(chǔ)。通過單分子技術(shù)和液相核磁共振技術(shù)，我們發(fā)現(xiàn)TCR在不同的抗原刺激下會產(chǎn)生不一樣的開放性構(gòu)象，從而對Lck激酶有不同程度的招募;隨后Lck對TCR上的多個(gè)酪氨酸位點(diǎn)進(jìn)行選擇性磷酸化，產(chǎn)生抗原特異性的磷酸化模式并引發(fā)不同的T細(xì)胞效應(yīng)功能(圖2，Cell Research 2017，PNAS 2017)。
　　圖2. TCR結(jié)構(gòu)多態(tài)性模型。TCR可以在不同抗原刺激下產(chǎn)生不同的開放性構(gòu)象，從而引發(fā)特異性的下游信號通路，使得T細(xì)胞獲得不同的效應(yīng)功能。這個(gè)模型解釋了T細(xì)胞獲得抗原特異性的信號基礎(chǔ)。
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　　我們同樣研究了T細(xì)胞的共抑制受體PD-1。T細(xì)胞在腫瘤微環(huán)境中會表現(xiàn)出功能耗竭的狀態(tài)，并伴隨著PD-1的異常高表達(dá)。目前在臨床上應(yīng)用的PD-1或PD-L1抗體就是通過阻滯PD-1的抑制性信號，進(jìn)而增強(qiáng)T細(xì)胞的抗腫瘤活性。我們發(fā)現(xiàn)了PD-1的降解機(jī)制及其在抗腫瘤過程中的重要性 (Nature 2018)。活化T細(xì)胞表面的PD-1會經(jīng)歷內(nèi)吞、泛素化和蛋白酶體的降解等一系列過程。我們找到了介導(dǎo)PD-1泛素化的E3連接酶FBXO38。在Fbxo38條件性敲除的小鼠體內(nèi)腫瘤生長的會更快，腫瘤浸潤T細(xì)胞的PD-1表達(dá)水平也更高。而PD-1抗體治療有效抑制了FBXO38缺失小鼠體內(nèi)腫瘤的生長，揭示了PD-1是FBXO38作用的直接靶點(diǎn)。FBXO38對PD-1表達(dá)量的調(diào)控為阻滯PD-1的抑制性信號提供了一個(gè)新的角度，也為針對PD-1的抗腫瘤藥物的研發(fā)提供新的思路。
　　2. 腫瘤免疫治療
　　近年來，本課題組利用自己在免疫受體和脂質(zhì)調(diào)控方面的基礎(chǔ)知識，提出了全新的腫瘤免疫治療理論及策略。一方面我們認(rèn)為通過調(diào)控T細(xì)胞的代謝狀態(tài)可以讓其獲得更強(qiáng)的效應(yīng)功能。我們發(fā)現(xiàn)膽固醇儲存通路的關(guān)鍵調(diào)節(jié)酶ACAT1是一個(gè)很好的調(diào)控靶點(diǎn)，抑制ACAT1的活性可以大大提高CD8+ T細(xì)胞(又名殺傷性T細(xì)胞)的抗腫瘤功能。其機(jī)理是ACAT1被抑制后，殺傷性T細(xì)胞膜上的游離膽固醇水平提高，從而讓TCR的聚集程度和信號轉(zhuǎn)導(dǎo)能力提高并使得T細(xì)胞的殺傷性免疫突觸形成更加有效。我們進(jìn)一步利用ACAT1的小分子抑制劑Avasimibe在動(dòng)物模型中治療多種腫瘤，發(fā)現(xiàn)該抑制劑具有很好的抗腫瘤效應(yīng);并且Avasimibe與現(xiàn)有的腫瘤免疫治療臨床藥物anti-PD-1聯(lián)用后效果更佳。Avasimibe曾經(jīng)作為心血管疾病的藥物進(jìn)行過三期臨床試驗(yàn)，雖然這個(gè)小分子抑制劑對動(dòng)脈粥樣硬化沒有明顯的治療效果，但是它具有很好的人體安全性，因此Avasimibe具有很好的潛力被開發(fā)成抗腫瘤藥物(Nature 2016，中國生命科學(xué)十大進(jìn)展)。
- 　　圖3. 基于膽固醇代謝調(diào)控的腫瘤免疫治療新方法。膽固醇酯化酶ACAT1可以將細(xì)胞內(nèi)的游離膽固醇轉(zhuǎn)化為膽固醇酯。抑制CD8+ T細(xì)胞的ACAT1活性可以使細(xì)胞質(zhì)膜的游離膽固醇水平上升，從而使得TCR信號增強(qiáng)并讓殺傷性免疫突觸更成熟。T細(xì)胞腫瘤抗原免疫應(yīng)答由此變得更加高效。
　　
　　另一方面我們基于CD3e 蛋白的多重信號功能發(fā)展了一種新的CAR-T細(xì)胞治療技術(shù)，可以提高細(xì)胞的抗腫瘤功能并降低細(xì)胞因子風(fēng)暴的風(fēng)險(xiǎn)。通過建立絕對定量質(zhì)譜系統(tǒng)，我們對CD3分子內(nèi)的所有酪氨酸位點(diǎn)定量并發(fā)現(xiàn)CD3e ITAM呈現(xiàn)出獨(dú)特的單磷酸化的模式。進(jìn)一步的研究發(fā)現(xiàn)，CD3e ITAM可以特異性的招募抑制性激酶Csk來抑制Lck介導(dǎo)的磷酸化過程，表明天然的抗原受體TCR同時(shí)具有活化元件(CD3z)和調(diào)控元件(CD3e)，具有信號自我調(diào)控的能力。目前臨床上使用的CAR-T細(xì)胞，其人工合成的抗原受體CAR卻只利用了CD3z。當(dāng)我們將CD3e加入至臨床上使用的CAR中后，CAR-T細(xì)胞的抗腫瘤能力得到了增強(qiáng)。從機(jī)制的角度來看，CD3e中的ITAM基序可以招募Csk來下調(diào)CAR-T細(xì)胞的細(xì)胞因子的分泌水平，BRS基序可以招募p85進(jìn)而增強(qiáng)CAR-T細(xì)胞的生長持續(xù)性。因此在CAR中加入了CD3e可以引入更豐富的信號調(diào)控機(jī)制，從而提升CAR-T的整體表現(xiàn)，為未來的CAR-T細(xì)胞治療提供新的發(fā)展方向(Cell 2020，中國生命科學(xué)十大進(jìn)展)。
　　圖4. 基于CD3e 蛋白多重信號功能而設(shè)計(jì)的新型CAR-T細(xì)胞療法。TCR的CD3e 鏈具有特殊的信號轉(zhuǎn)導(dǎo)功能，可以同時(shí)招募抑制性分子Csk和活化性分子PI3K。將CD3e 胞內(nèi)區(qū)加入臨床使用的CAR序列中，可使得CAR-T細(xì)胞生長持續(xù)性更好，抗腫瘤功能更強(qiáng)，并且細(xì)胞因子釋放綜合癥的風(fēng)險(xiǎn)降低。
　　綜上所述，本研究組在T細(xì)胞的基礎(chǔ)研究中發(fā)現(xiàn)了T細(xì)胞活化的新分子機(jī)制，同時(shí)在免疫受體信號和代謝調(diào)控兩個(gè)角度發(fā)展了新的腫瘤免疫治療方法。今后我們將主要研究在不同生理和病理環(huán)境下的T細(xì)胞脂代謝特征，并且尋找新的“代謝檢查點(diǎn)”用于代謝調(diào)控，同時(shí)進(jìn)行CAR-T細(xì)胞的功能機(jī)制研究，為未來CAR-T細(xì)胞的設(shè)計(jì)與臨床應(yīng)用提供新的思路與發(fā)展方向。?

承擔(dān)科研項(xiàng)目情況：

代表論著：

( ^#first author, ^*corresponding author )
1. Jiang Y^#, Dai A^#, Huang Y^#, Li H^#, Cui J^#, Yang H, Si L, Jiao T, Ren Z, Zhang Z, Mou S, Zhu H, Guo W, Huang Q, Li Y, Xue M, Jiang J, Wang F, Li L, Zhong Q, Wang K, Liu B, Wang J, Fan G, Guo J, Chen L, Workman CJ, Shen Z^*, Kong Y^*, Vignali DAA^*,?Xu C^*, Wang H^*. Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs.?Cell, 188(9):2354-2371.e18, 2025.
2. Xu XY^#, Chen H^#, Ren Z^#, Xu XM^#, Wu W, Yang H, Wang J, Zhang Y, Zhou Q, Li H, Zhang S, Wang H*,?Xu C*. Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity.?Immunity,?57(12): 2755-2771, 2024.
3. Shi X, He X, Xu C. Charge-based immunoreceptor signalling in health and disease.?Nature Reviews Immunology,?25(4):298-311, 2024.
4. Ren Z^#, Wang K^#, Zhang Y^#, Chen H, Zhu Y, Li H, Lou J^*, Wang H^*,?Xu C^*.?Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity.?Cell Chemical Biology, 31(5):920-931.e6, 2024.
5. Shi Y, Zheng X, Peng H,?Xu C, Sun R, Tian Z^*, Sun H^*, Wang X^*. The E3 Ubiquitin Ligase FBXO38 Maintains the Antitumor Function of Natural Killer Cells by Sustaining IL15R Signaling.?Cancer Immunology Research?12(10):1438-1451,2024.
6. Bai Y^#, Li T^#, Wang Q^#, You W^#,?Yang H,?Xu X, Li Z, Zhang Y, Yan C, Yang L, Qiu J, Liu Y, Chen S,?Wang D,?Huang B, Liu K, Song B, Wang Z, Li K, Liu X, Wang G, Yang W, Chen J, Hao P, Zhang Z, Wang Z^*, Zhu Z^*,?Xu C^*,?Shaping immune landscape of colorectal cancer by cholesterol metabolites,?EMBO Molecular Medicine?16(2):334-360, 2024.
7. Guo J,?Xu C^*,?Screening for the next-generation T cell therapies.?Cancer Cell, 37(5): 627-629, 2020.
8. Fan Z^#, Tian Y^#, Chen Z, Liu L, Zhou Q, He J, Coleman J, Dong C, Li N, Huang J,?Xu C, Zhang Z, Gao S, Zhou P^*, Ding K^*, Chen L^*,?Blocking interaction between SHP2 and PD-1 denotes a novel opportunity for developing PD-1 inhibitors.?EMBO molecular medicine, e11571, 2020.
9. He X,?Xu C^*, PD-1: A Driver or Passenger of T Cell Exhaustion??Molecular Cell, 77(5): 930-931, 2020.
10. Huang B, Song B,?Xu C^*.?Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities.?Nature Metabolism, 2: 132-141, 2020.
11. Xu X^#, Li H^#,?Xu, C^*.?Structural understanding of T cell receptor triggering.?Cellular & Molecular Immunology, 17(3): 193-202, 2020.
12. Li H*, Yan C, Guo J, Xu C*. Ionic protein–lipid interactions at the plasma membrane regulate the structure and function of immunoreceptors. Advances in Immunology, 144 pp 65-85, 2019.
13. Wu P, Zhang T, Liu B, Fei P, Cui L, Qin R, Zhu H, Yao D, Martinez R, Hu W, An C, Zhang Y, Liu J, Shi J, Fan J, Yin W, Sun J, Zhou C, Zeng X, Xu C, Wang J, Evavold B, Zhu C, Chen W*, Lou J*. Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition. Molecular Cell. 73(5):1015-1027, 2019.
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