Lethal renal cell carcinoma sub-clones: Defining mechanisms of tumour evolution, treatment resistance and immune escape.

致命性肾细胞癌亚克隆：定义肿瘤进化、治疗抵抗和免疫逃逸的机制。

• 批准号: MR/P014712/2
• 负责人: Kevin Litchfield
• 金额: $ 21.01万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP014712%2F2
• 关键词: Lethal; renal; cell; carcinoma; sub

Kidney cancers have doubled in the UK over last 40 years, with >11,000 new cases annually and >4,200 deaths. Despite increased early detection the 5-year survival rates remain poor at 56%, with average survival of only ~18 months for advanced disease. Death is typically caused by disease spread to distal organs in a process called metastasis. While new drugs have been introduced to treat advanced metastatic disease, they are mainly used as palliative treatment options to delay rather than prevent mortality. This is due to drug resistance, which occurs in almost all patients, on average within 9 months. A major factor contributing to drug resistance is the extraordinary diversity found within tumours, caused by a pattern of continuous genetic mutation as the tumour grows. This means a tumour can actually be made up of many sub-tumours (called "subclones"), each of which is different. Treatment typically fails when some but not all of these "subclones" can be destroyed, and the ones left then grow back stronger causing terminal disease (called "lethal subclones").This research will study how "lethal subclones" grow, how they spread across the body and how they resist drugs. The study will involve 320 kidney cancer patients, starting before drug treatment and will analyse DNA from their primary kidney tumour, which will be physically cut into a series of separate subregions (on average 7 per patient). This allows the different "subclones" to be looked at individually. As disease progresses and/or becomes treatment resistant, additional DNA will be analysed from tumours in other organs (metastases), from blood/urine samples as well as from autopsy tissue. This will allow the "lethal subclones" to be pinpointed, both before and after disease progression/drug resistance. By pinpointing the "lethal sub-clones" and tracking them through the disease course, it is anticipated that their strengths and weaknesses can be identified, generating fundamental biological knowledge to support the development of new treatment options. Another aim of this project is to develop a new cost effective diagnostic test to detect "lethal subclones", meaning high risk patients can be identified upfront and more aggressive treatment plans considered.In the future a new generation of treatments called "immunotherapies" hold significant clinical promise to tackle "lethal subclones" and increase survival rates for kidney cancer. In other tumour types, such as skin, lung and blood cancers, breakthrough results have already been achieved in the last 5 years. The immune system plays an active role in kidney tumours, with white blood cells (lymphocytes) able to penetrate into the tumour and kill cancer cells. This process can be exploited therapeutically, either by raising the activity level of white blood cells or introducing more of them to attack the tumour. The great benefit of this approach, as compared to traditional drugs, is that the white blood cells are a living treatment that can adapt and keep up with the changing cancer cells. Immunotherapies have been previously tested in advanced kidney cancer patients with mixed results. A modest fraction of patients showed remarkable results (10+ years cancer free) however the majority failed to derive any benefit. The reasons for this are unclear, due to our limited biological understanding of how the immune system operates inside kidney tumours. The second half of this project will conduct a detailed study of the immune system within kidney tumours. The DNA analysis from above will be complimented by RNA analysis and a technique called "multiplex immunohistochemistry", to map the location and activity of different types of white blood cell. This will be the biggest study of its kind in kidney cancer patients to date and aims to reveal how the immune system behaves in response to kidney cancer, providing insights to support the development of new immunotherapies.

过去 40 年来，英国的肾癌发病率翻了一番，每年新增病例超过 11,000 例，死亡人数超过 4,200 例。尽管早期检测有所增加，但 5 年生存率仍然很低，仅为 56%，晚期疾病的平均生存期仅为约 18 个月。死亡通常是由疾病扩散到远端器官引起的，这一过程称为转移。虽然已推出新药来治疗晚期转移性疾病，但它们主要用作姑息治疗选择，以延迟而不是预防死亡。这是由于几乎所有患者平均在 9 个月内就会出现耐药性。造成耐药性的一个主要因素是肿瘤内发现的非凡多样性，这是由肿瘤生长过程中持续基因突变的模式引起的。这意味着肿瘤实际上可以由许多子肿瘤（称为“亚克隆”）组成，每个子肿瘤都是不同的。当这些“亚克隆”中的一些但不是全部被破坏，而剩下的亚克隆又长得更强，导致绝症（称为“致命亚克隆”）时，治疗通常会失败。这项研究将研究“致命亚克隆”如何生长、它们如何在全身传播以及它们如何抵抗药物。该研究将涉及 320 名肾癌患者，从药物治疗前开始，分析他们原发性肾肿瘤的 DNA，这些肿瘤将被物理切割成一系列独立的子区域（平均每个患者 7 个）。这使得可以单独查看不同的“亚克隆”。随着疾病进展和/或产生治疗耐药性，将从其他器官的肿瘤（转移）、血液/尿液样本以及尸检组织中分析额外的 DNA。这将允许在疾病进展/耐药性之前和之后精确定位“致命亚克隆”。通过查明“致命亚克隆”并在整个疾病过程中跟踪它们，预计可以识别它们的优点和缺点，从而产生基础生物学知识来支持新治疗方案的开发。该项目的另一个目标是开发一种新的具有成本效益的诊断测试来检测“致命亚克隆”，这意味着可以提前识别高风险患者并考虑更积极的治疗计划。未来，称为“免疫疗法”的新一代治疗方法具有解决“致命亚克隆”并提高肾癌生存率的重大临床前景。在其他肿瘤类型，如皮肤癌、肺癌和血癌中，过去五年已经取得了突破性的成果。免疫系统在肾肿瘤中发挥着积极作用，白细胞（淋巴细胞）能够渗透到肿瘤并杀死癌细胞。这个过程可以通过提高白细胞的活性水平或引入更多的白细胞来攻击肿瘤来进行治疗。与传统药物相比，这种方法的巨大好处是白细胞是一种活的治疗方法，可以适应并跟上癌细胞的变化。免疫疗法之前已在晚期肾癌患者中进行过测试，结果好坏参半。一小部分患者显示出显着的效果（10 年以上无癌症），但大多数患者未能获得任何益处。由于我们对肾肿瘤内免疫系统如何运作的生物学了解有限，其原因尚不清楚。该项目的后半部分将对肾肿瘤内的免疫系统进行详细研究。上述 DNA 分析将得到 RNA 分析和一种称为“多重免疫组织化学”的技术的补充，以绘制不同类型白细胞的位置和活性。这将是迄今为止针对肾癌患者进行的最大规模的此类研究，旨在揭示免疫系统如何应对肾癌，为支持新免疫疗法的开发提供见解。

项目成果

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.

• DOI: 10.1016/j.cell.2021.01.002
• 发表时间: 2021-02-04
• 期刊: Cell
• 影响因子: 64.5
• 作者: Litchfield K;Reading JL;Puttick C;Thakkar K;Abbosh C;Bentham R;Watkins TBK;Rosenthal R;Biswas D;Rowan A;Lim E;Al Bakir M;Turati V;Guerra-Assunção JA;Conde L;Furness AJS;Saini SK;Hadrup SR;Herrero J;Lee SH;Van Loo P;Enver T;Larkin J;Hellmann MD;Turajlic S;Quezada SA;McGranahan N;Swanton C
• 通讯作者: Swanton C

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study.

• DOI: 10.1038/s41559-021-01586-x
• 发表时间: 2022-01
• 期刊: Nature ecology & evolution
• 影响因子: 16.8
• 作者: Fu X;Zhao Y;Lopez JI;Rowan A;Au L;Fendler A;Hazell S;Xu H;Horswell S;Shepherd STC;Spencer CE;Spain L;Byrne F;Stamp G;O'Brien T;Nicol D;Augustine M;Chandra A;Rudman S;Toncheva A;Furness AJS;Pickering L;Kumar S;Koh DM;Messiou C;Dafydd DA;Orton MR;Doran SJ;Larkin J;Swanton C;Sahai E;Litchfield K;Turajlic S;TRACERx Renal Consortium;Bates PA
• 通讯作者: Bates PA

Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.

• DOI: 10.1038/s41591-020-0900-x
• 发表时间: 2020-07
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: AbdulJabbar K;Raza SEA;Rosenthal R;Jamal-Hanjani M;Veeriah S;Akarca A;Lund T;Moore DA;Salgado R;Al Bakir M;Zapata L;Hiley CT;Officer L;Sereno M;Smith CR;Loi S;Hackshaw A;Marafioti T;Quezada SA;McGranahan N;Le Quesne J;TRACERx Consortium;Swanton C;Yuan Y
• 通讯作者: Yuan Y

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

• DOI: 10.1038/s43018-020-0066-y
• 发表时间: 2020-05-01
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Ghorani, Ehsan;Reading, James L.;Quezada, Sergio A.
• 通讯作者: Quezada, Sergio A.

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

• DOI: 10.1016/j.ccell.2021.10.001
• 发表时间: 2021-11-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Au L;Hatipoglu E;Robert de Massy M;Litchfield K;Beattie G;Rowan A;Schnidrig D;Thompson R;Byrne F;Horswell S;Fotiadis N;Hazell S;Nicol D;Shepherd STC;Fendler A;Mason R;Del Rosario L;Edmonds K;Lingard K;Sarker S;Mangwende M;Carlyle E;Attig J;Joshi K;Uddin I;Becker PD;Sunderland MW;Akarca A;Puccio I;Yang WW;Lund T;Dhillon K;Vasquez MD;Ghorani E;Xu H;Spencer C;López JI;Green A;Mahadeva U;Borg E;Mitchison M;Moore DA;Proctor I;Falzon M;Pickering L;Furness AJS;Reading JL;Salgado R;Marafioti T;Jamal-Hanjani M;PEACE Consortium;Kassiotis G;Chain B;Larkin J;Swanton C;Quezada SA;Turajlic S;TRACERx Renal Consortium
• 通讯作者: TRACERx Renal Consortium