Identification and targeting of early T cell dysfunction in pulmonary preinvasive neoplasia
Lead Research Organisation:
University College London
Department Name: Haematology
Abstract
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 cancer
3. 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.
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 cancer
3. 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.
People |
ORCID iD |
James Reading (Principal Investigator / Fellow) |
Publications
Abbosh C
(2023)
Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.
in Nature
Al Bakir M
(2023)
The evolution of non-small cell lung cancer metastases in TRACERx.
in Nature
Al-Sawaf O
(2023)
Body composition and lung cancer-associated cachexia in TRACERx
in Nature Medicine
Barnes JL
(2023)
Early human lung immune cell development and its role in epithelial cell fate.
in Science immunology
Frankell AM
(2023)
The evolution of lung cancer and impact of subclonal selection in TRACERx.
in Nature
Hasan AMM
(2023)
Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.
in Nature communications
Hill W
(2023)
Lung adenocarcinoma promotion by air pollutants.
in Nature
Holm JS
(2022)
Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma.
in Nature communications
Hwang ES
(2023)
Pre-cancer: From diagnosis to intervention opportunities.
in Cancer cell
Description | Group development I have established a fully-fledged research group at my host institute, currently 7 staff, rising to 10 by the end of the year. My staff have been trained in computational courses and/or cutting edge in vitro T cell immunology technology and are embedded in peer to peer learning fora and have now each presented at internal, department and/or national conferences. I have undergone training and development at UCL and have started to develop a new theme of carcinogesis research and an immuno-oncology programme whilst consolidating my position as theme lead of Immunology in the CRUK lung cancer centre of excellence. Research progress Our research has progressed significantly since the award started in June 2022. Consistent with Aim 1 (objectives 1.1-1.2) we have discovered and integrated two types of immune derived signals in the blood of patients with progressive pre-malignant lesions of the lung. These signals have now formed the back bone of a prototype biomarker, the IP for which has been filed (see relevant section). Validation of this biomarker is ongoing as per objective 1.3. Our work in Aim 2 thus far has led to the discover that mutated, but non-cancerous cells of the airways may evoke an immune response. This work, if further substantiated, will lead to a paradigm shift in our fundamental understanding of how and when the immune system first recognises cancer. There are two major scientific reports being prepared for publication as a result. Societal impact I have taken on the position of co-lead in a new program of widening participation for STEM research for disadvantaged youths, the first event of the ATOMIC programme will occur in July 2023. |
Exploitation Route | Industry led development of our cancer early detection prototype biomarker, should results be further extended. |
Sectors | Communities and Social Services/Policy,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The presentation of our work at international conferences (CICON 2022; http://www.cancerimmunotherapyconference.org/s/Meeting-Agenda-092922_CICON22.pdf ) has galvanised research efforts in this space and contributed to the emergence of Immune cancer early detection (ICEdx) as a field. |
First Year Of Impact | 2022 |
Sector | Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
Description | 2022CRUK City of London Centre 4 Year PhD studentship |
Amount | £151,306 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2022 |
End | 08/2026 |
Description | A multiomic T cell differentiation index (TEDI) for non-invasive early detection of lung and renal cancer (CRUK early detection project award) |
Amount | £513,339 (GBP) |
Funding ID | EDDPJT-Nov22/100042 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2023 |
End | 06/2026 |
Description | BRC Funding for Project ID - 6766671 Reading BC and Tech Student |
Amount | £230,000 (GBP) |
Funding ID | BRC907/CN/JR/101330 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 12/2022 |
End | 12/2026 |
Description | Clinical Research and Development Committee Research Funding from the BRC and UCLH Charities - Fast Track Grant |
Amount | £39,593 (GBP) |
Funding ID | CRDC Reference: F226 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 04/2022 |
End | 04/2023 |
Description | MRC DTP PhD |
Amount | £67,842 (GBP) |
Funding ID | 170890 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2022 |
End | 09/2025 |
Description | NIMBLE |
Organisation | Royal Marsden Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Immunological analysis of blood samples |
Collaborator Contribution | Provision of samples |
Impact | None yet |
Start Year | 2022 |
Description | Prof Maxine Tran |
Organisation | University College London |
Department | Division of Surgery & Interventional Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Preliminary flow cytometry analysis of blood samples from patients with malignant vs benign renal tumours |
Collaborator Contribution | Provision of 160 PBMC samples from patients with renal cancer |
Impact | CRUK early detection project award JR as lead £0.5m |
Start Year | 2022 |
Description | Prof Sam Janes - lung neoplasia |
Organisation | University College London |
Department | Lungs for Living Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | 1. High dimensional flow cytometry profiling of blood samples from patients with preinvasive pulmonary neoplasia 2. TCRseq profiling of blood samples from patients with preinvasive pulmonary neoplasia 3. TCRseq profiling of pre-malignant lesion samples from patients with preinvasive pulmonary neoplasia 4. Single cell RNAseq analysis of lesion biopsies from patients with preinvasive pulmonary neoplasia 5. Joint laboratory meetings once every 2 months 6. Generation and initial filing of IP 7. Led a successful bid for a CRUK early detection project award 8. Co-ordinated a bid for a successful consortium grant for ACED 9. Guidance and supervision on Immunology |
Collaborator Contribution | 1. Provision of biospecimens including PBMCs, bronchial biopsies 2. Provision of human and mouse scRNAseq data 3. Provision of spatial transcriptomics data 4. Provision of whole exome sequencing data 5. Joint laboratory meetings once every 2 months 6. Guidance and supervision on respiratory medicine |
Impact | Cancer Research UK Early Detection Project Award Lead Investigator JR, CO-Is Sam Janes and Maxine Tran: https://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/recently-funded-awards#Population%20Research%20Committee: £0.5m. ACED consortium award: Exploiting the immune system for cancer early detection; £1.5m for UCL, £0.5m for JR lab Generation of IP: The T cell Early Detection Index (TEDI) created by my group has undergone provisional filing via UCLBusiness All are multidisciplinary - combining Respiratory Medicine, Immunology, Oncology, Informatics |
Start Year | 2022 |
Description | Sine Hadrup |
Organisation | Technical University of Denmark |
Country | Denmark |
Sector | Academic/University |
PI Contribution | Supervision of T cell biology |
Collaborator Contribution | Reagents and technical guidance |
Impact | Publication https://www.nature.com/articles/s41467-022-29342-0 |
Start Year | 2022 |
Description | TRACERx - Charles Swanton |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Analysis of circulating T cells during lung cancer progression |
Collaborator Contribution | Provision of samples |
Impact | BRC Fast track award £40'000 |
Start Year | 2022 |
Description | CRICK Open day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | PhD student Amber Rogers (CRUK COL program) presented work which is overlapping with the laboratory's main aims, supported by the UKRI award. This was a poster presented to patient groups and the public at the Francis Crick institute. |
Year(s) Of Engagement Activity | 2023 |