Identification and targeting of early T cell dysfunction in pulmonary preinvasive neoplasia

肺浸润前肿瘤早期 T 细胞功能障碍的识别和靶向

• 批准号: MR/W011786/1
• 负责人: James Reading
• 金额: $ 194.99万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW011786%2F1
• 关键词: Identification; targeting; early; cell; dysfunction

Cancer is initiated by mutations that often arise from exposure to environmental factors, such as UV light or cigarette smoke. The immune system eliminates the vast majority of mutant cells that develop as we age but dysfunction of this defence allows some mutant cells to break through into cancer. If we could detect pre-cancerous growths at an early stage and rapidly repair this underlying immune dysfunction, we could reawaken mutation-specific immunity to destroy small tumours before they advance or prevent tumour formation altogether. However, we lack robust methods to detect pre-cancerous growth for many cancer types and the identity of these crucial defects in the immune system remains a mystery. This presents two urgent scientific challenges:1. How can we detect tumours in early or pre-cancerous stages?2. How can we identify and repair the early defects in our immune system that allow mutant cells to progress to cancer?This UKRI FLF application sets out an innovative research programme that will be the first to study the immune response to mutant cells in pre-cancerous lesions of the lungs at never-before-seen scale and depth. Using a globally unique set of clinical samples from patients with 'preinvasive' lung lesions I will study key killer 'T cells' which recognise pre-cancerous growths. Using experimental, cutting-edge technology I have developed over the last 5 years I aim to pinpoint defects in mutation-specific T cells to refine a portfolio of precision, prototype drugs to resurrect their killer functions. At the same time, I will attempt to hi-jack the dysfunction of killer T cells as a method of early lung cancer detection, thus weaponising the failing immune system in pre-cancerous disease into a clinical strategy to track and target dangerous lesions to stop cancer in its nascent form.My own research, and that of others has shown that both of these approaches may be potent clinical strategies with the potential to save a significant number of lives. Firstly, early detection of lung cancer reduces deaths by approximately 25%, because we can deploy treatment before tumours have a chance to spread. Secondly fixing tumour-associated T cell dysfunction at an earlier stage in animals and humans is more effective than doing so later and can generate long-lived potentially, curative immune responses that destroy tumours and may protect patients from mutated cells that arise in the future. Whilst my laboratory are focussing this series of experiments in preinvasive lung disease, it has much wider ranging impact. For example, we know that T cell dysfunction in later stages is similar across multiple cancers and that current 'immunotherapies' have an effect on several types of cancer. Moreover, we have preliminary results suggesting that tracking tumours via dysfunctional T cells in the blood is feasible. To conduct this study in preinvasive lung disease I will test three hypotheses: 1. Early T cell dysfunction can be used as a blood-based method of detecting pre-cancerous growths in the lung 2. Killer T cells recognise the mutated cells that give rise to cancer3. Defects in mutation-specific killer T cells can be identified and repaired to restore their function. This work will develop novel tests for early cancer detection and prototype drugs to pioneer future clinical strategies, paving the way for a new era of cancer medicines I have coined Early Intervention Immunotherapy and Cancer Immunoprevention.

癌症是由暴露于环境因素（如紫外线或香烟烟雾）引起的突变引发的。免疫系统消除了随着年龄增长而发展的绝大多数突变细胞，但这种防御功能的障碍允许一些突变细胞突破进入癌症。如果我们能够在早期阶段检测到癌前生长并快速修复这种潜在的免疫功能障碍，我们就可以重新唤醒突变特异性免疫力，在小肿瘤发展之前摧毁它们，或者完全阻止肿瘤形成。然而，我们缺乏强大的方法来检测许多癌症类型的癌前生长，并且免疫系统中这些关键缺陷的身份仍然是一个谜。这提出了两个紧迫的科学挑战：1。我们如何在早期或癌前阶段检测肿瘤？2.我们如何识别和修复免疫系统中允许突变细胞发展为癌症的早期缺陷？这项UKRI FLF申请提出了一项创新的研究计划，该计划将首次以前所未有的规模和深度研究肺部癌前病变中突变细胞的免疫反应。使用全球唯一的一组来自“浸润前”肺部病变患者的临床样本，我将研究识别癌前生长的关键杀手“T细胞”。利用我在过去5年中开发的实验性尖端技术，我的目标是精确定位突变特异性T细胞的缺陷，以完善一系列精确的原型药物，以恢复其杀手功能。与此同时，我将尝试劫持杀伤T细胞的功能障碍作为早期肺癌检测的方法，从而将癌前疾病中失败的免疫系统武器化为临床策略，以跟踪和靶向危险病变，以阻止癌症的新生形式。我自己的研究，其他人的研究表明，这两种方法都可能是有效的临床策略，有可能挽救大量生命。首先，肺癌的早期发现可以将死亡率降低约25%，因为我们可以在肿瘤有机会扩散之前部署治疗。其次，在动物和人类的早期阶段修复肿瘤相关的T细胞功能障碍比以后这样做更有效，可以产生长期的潜在治疗性免疫反应，摧毁肿瘤，并可能保护患者免受未来出现的突变细胞的影响。虽然我的实验室专注于这一系列的实验，在前侵袭性肺部疾病，它有更广泛的影响。例如，我们知道，多种癌症的晚期T细胞功能障碍是相似的，目前的“免疫疗法”对几种类型的癌症有影响。此外，我们的初步结果表明，通过血液中功能失调的T细胞追踪肿瘤是可行的。为了在浸润前肺部疾病中进行这项研究，我将测试三个假设：1。早期T细胞功能障碍可用作检测肺中癌前生长的基于血液的方法2。杀伤T细胞识别引起癌症的突变细胞3。突变特异性杀伤T细胞的缺陷可以被识别和修复，以恢复其功能。这项工作将开发用于早期癌症检测的新测试和原型药物，以开拓未来的临床策略，为癌症药物的新时代铺平道路，我创造了早期干预免疫治疗和癌症免疫预防。

项目成果

Pre-cancer: From diagnosis to intervention opportunities.

癌症前期：从诊断到干预机会。

• DOI: 10.1016/j.ccell.2023.03.012
• 发表时间: 2023
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Hwang ES

Early human lung immune cell development and its role in epithelial cell fate

早期人肺免疫细胞发育及其在上皮细胞命运中的作用

• DOI: 10.1101/2022.12.13.519713
• 发表时间: 2022
• 作者: Barnes J

The evolution of lung cancer and impact of subclonal selection in TRACERx.

• DOI: 10.1038/s41586-023-05783-5
• 发表时间: 2023-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Frankell, Alexander M.;Dietzen, Michelle;Al Bakir, Maise;Lim, Emilia L.;Karasaki, Takahiro;Ward, Sophia;Veeriah, Selvaraju;Colliver, Emma;Huebner, Ariana;Bunkum, Abigail;Hill, Mark S.;Grigoriadis, Kristiana;Moore, David A.;Black, James R. M.;Liu, Wing Kin;Thol, Kerstin;Pich, Oriol;Watkins, Thomas B. K.;Naceur-Lombardelli, Cristina;Cook, Daniel E.;Salgado, Roberto;Wilson, Gareth A.;Bailey, Chris;Angelova, Mihaela;Bentham, Robert;Martinez-Ruiz, Carlos;Abbosh, Christopher;Nicholson, Andrew G.;Le Quesne, John;Biswas, Dhruva;Rosenthal, Rachel;Puttick, Clare;Hessey, Sonya;Lee, Claudia;Prymas, Paulina;Toncheva, Antonia;Smith, Jon;Xing, Wei;Nicod, Jerome;Price, Gillian;Kerr, Keith M.;Naidu, Babu;Middleton, Gary;Blyth, Kevin G.;Fennell, Dean A.;Forster, Martin D.;Lee, Siow Ming;Falzon, Mary;Hewish, Madeleine;Shackcloth, Michael J.;Lim, Eric;Benafif, Sarah;Russell, Peter;Boleti, Ekaterini;Krebs, Matthew G.;Lester, Jason F.;Papadatos-Pastos, Dionysis;Ahmad, Tanya;Thakrar, Ricky M.;Lawrence, David;Navani, Neal;Janes, Sam M.;Dive, Caroline;Blackhall, Fiona H.;Summers, Yvonne;Cave, Judith;Marafioti, Teresa;Herrero, Javier;Quezada, Sergio A.;Peggs, Karl S.;Schwarz, Roland F.;Van Loo, Peter;Miedema, Daniel M.;Birkbak, Nicolai J.;Hiley, Crispin T.;Hackshaw, Allan;Zaccaria, Simone;Jamal-Hanjani, Mariam;McGranahan, Nicholas;Swanton, Charles;Bajaj, Amrita;Nakas, Apostolos;Sodha-Ramdeen, Azmina;Ang, Keng;Tufail, Mohamad;Chowdhry, Mohammed Fiyaz;Scotland, Molly;Boyles, Rebecca;Rathinam, Sridhar;Wilson, Claire;Marrone, Domenic;Dulloo, Sean;Matharu, Gurdeep;Shaw, Jacqui A.;Riley, Joa;Primrose, Lindsay;Cheyne, Heather;Khalil, Mohammed;Richardson, Shirley;Cruickshank, Tracey;Gilbert, Kayleigh;Patel, Akshay J.;Osman, Aya;Lacson, Christer;Langman, Gerald;Shackleford, Helen;Djearaman, Madava;Kadiri, Salma;Leek, Angela;Hodgkinson, Jack Davies;Totten, Nicola;Montero, Angeles;Smith, Elaine;Fontaine, Eustace;Granato, Felice;Doran, Helen;Novasio, Juliette;Rammohan, Kendadai;Joseph, Leena;Bishop, Paul;Shah, Rajesh;Moss, Stuart;Joshi, Vijay;Crosbie, Philip;Gomes, Fabio;Brown, Kate;Carter, Mathew;Chaturvedi, Anshuman;Priest, Lynsey;Oliveira, Pedro;Lindsay, Colin R.;Clipson, Alexandra;Tugwood, Jonathan;Kerr, Alastair;Rothwell, Dominic G.;Kilgour, Elaine;Aerts, Hugo J. W. L.;Kaufmann, Tom L.;Szallasi, Zoltan;Kisistok, Judit;Sokac, Mateo;Diossy, Miklos;Demeulemeester, Jonas;Stewart, Aengus;Magness, Alastair;Rowan, Andrew;Karamani, Angeliki;Chain, Benny;Campbell, Brittany B.;Castignani, Carla;Weeden, Clare E.;Richard, Corentin;Pearce, David R.;Karagianni, Despoina;Levi, Dina;Hoxha, Elena;Larose Cadieux, Elizabeth;Nye, Emma;Gronroos, Eva;Galvez-Cancino, Felip;Athanasopoulou, Foteini;Gimeno-Valiente, Francisco;Kassiotis, George;Stavrou, Georgia;Mastrokalos, Gerasimos;Zhai, Haoran L.;Lowe, Helen L.;Matos, Ignacio;Goldman, Jacki;Reading, James L.;Rane, Jayant K.;Lam, Jie Min;Hartley, John A.;Enfield, Katey S. S.;Selvaraju, Kayalvizhi;Litchfield, Kevin;Ng, Kevin W.;Chen, Kezhong;Dijkstra, Krijn;Thakkar, Krupa;Ensell, Leah;Shah, Mansi;Vasquez, Marcos;Litovchenko, Maria;Werner Sunderland, Mariana;Leung, Michelle;Escudero, Mickael;Tanic, Miljana;Sivakumar, Monica;Kanu, Nnennaya;Chervova, Olga;Lucas, Olivia;Al-Sawaf, Othman;Hobson, Philip;Pawlik, Piotr;Stone, Richard Kevin;Hynds, Robert E.;Vendramin, Roberto;Saghafinia, Sadegh;Lopez, Saioa;Gamble, Samuel;Ung, Seng Kuong Anakin;Vanloo, Sharon;Boeing, Stefan;Beck, Stephan;Bola, Supreet Kaur;Denner, Tamara;Mourikis, Thanos P.;Spanswick, Victoria;Barbe, Vittorio;Lu, Wei-Ting;Hill, William;Wu, Yin;Naito, Yutaka;Ramsden, Zoe;Veiga, Catarina;Royle, Gary;Collins-Fekete, Charles-Antoine;Fraioli, Francesco;Ashford, Paul;Clark, Tristan;Borg, Elaine;Wilson, James;Procter, Alexander James;Ahmed, Asia;Taylor, Magali N.;Nair, Arjun;Patrini, Davide;Martinoni Hoogenboom, Emilie;Monk, Fleur;Holding, James W.;Choudhary, Junaid;Bhakhri, Kunal;Scarci, Marco;Hayward, Martin;Panagiotopoulos, Nikolaos;Gorman, Pat;Khiroya, Reena;Stephens, Robert C. M.;Wong, Yien Ning Sophia;Bandula, Steve;Sharp, Abigail;Smith, Sean;Gower, Nicole;Dhanda, Harjot Kaur;Chan, Kitty;Pilotti, Camilla;Leslie, Rachel;Grapa, Anca;Zhang, Hanyun;AbdulJabbar, Khalid;Pan, Xiaoxi;Yuan, Yinyin;Chuter, David;MacKenzie, Mairead;Chee, Serena;Alzetani, Aiman;Scarlett, Lydia;Richards, Jennifer;Ingram, Papawadee;Austin, Silvia;De Sousa, Paulo;Jordan, Simon;Rice, Alexandra;Raubenheimer, Hilgardt;Bhayani, Harshil;Ambrose, Lyn;Devaraj, Anand;Chavan, Hema;Begum, Sofina;Buderi, Silviu, I;Kaniu, Daniel;Malima, Mpho;Booth, Sarah;Fernandes, Nadia;Shah, Pratibha;Proli, Chiara;Danson, Sarah;Robinson, Lily;Dick, Craig;Kirk, Alan;Asif, Mo;Bilancia, Rocco;Kostoulas, Nikos;Thomas, Mathew
• 通讯作者: Thomas, Mathew

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

• DOI: 10.1038/s41586-023-05776-4
• 发表时间: 2023-04
• 期刊: Nature
• 影响因子: 64.8
• 作者: Abbosh C;Frankell AM;Harrison T;Kisistok J;Garnett A;Johnson L;Veeriah S;Moreau M;Chesh A;Chaunzwa TL;Weiss J;Schroeder MR;Ward S;Grigoriadis K;Shahpurwalla A;Litchfield K;Puttick C;Biswas D;Karasaki T;Black JRM;Martínez-Ruiz C;Bakir MA;Pich O;Watkins TBK;Lim EL;Huebner A;Moore DA;Godin-Heymann N;L'Hernault A;Bye H;Odell A;Roberts P;Gomes F;Patel AJ;Manzano E;Hiley CT;Carey N;Riley J;Cook DE;Hodgson D;Stetson D;Barrett JC;Kortlever RM;Evan GI;Hackshaw A;Daber RD;Shaw JA;Aerts HJWL;Licon A;Stahl J;Jamal-Hanjani M;TRACERx Consortium;Birkbak NJ;McGranahan N;Swanton C
• 通讯作者: Swanton C

Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma.

• DOI: 10.1038/s41467-022-29342-0
• 发表时间: 2022-04-11
• 期刊: Nature communications
• 影响因子: 16.6