ImmuneMetTx
Lead Research Organisation:
The Francis Crick Institute
Abstract
Immune checkpoint inhibitors (CPIs), which have revolutionised the treatment of metastatic NSCLC and other tumour types, increase the anti- tumour immune response through T-cell activation. However, clinical experience has revealed that more than 50% of patients present with intrinsic or develop acquired treatment resistance to immune therapies. It is unclear whether immunoediting, a set of processes that cause selection for cancer cells resilient to immune attacks, play an essential role in CPI resistance. To properly study immunoediting through cancer progression, it is essential to reconstruct the evolutionary history of cancer cell-intrinsic immunoediting processes - for example through loss of HLA alleles-, and the roles played by the tumour microenvironment in mediating immune selection pressures. To do that, comprehensive sampling and characterisation of a clinical cohort of primary tumours and the corresponding metastases are needed. Such datasets are scarce and where available, include data from only a few individuals
In this project, I aim to quantify mechanisms of immunoediting in longitudinal multi-region samples collected at the time of surgery, relapse, and autopsy to answer fundamental questions about how the immune system shapes cancer evolution and the role of immunoediting in CPI failure. This analysis will be made possible by the TRACERx, PEACE studies and the DARWIN II clinical trial, managed by the host lab. I will integrate different data, including 500X whole-exome sequencing, Imaging Mass Cytometry, evolutionary reconstruction and detailed clinical annotation, to do an unprecedented analysis of the spatial and temporal heterogeneity of immunoediting mechanisms, and how they relate to features of the cancer genome, transcriptome, tumour microenvironment and CPI responses.
In this project, I aim to quantify mechanisms of immunoediting in longitudinal multi-region samples collected at the time of surgery, relapse, and autopsy to answer fundamental questions about how the immune system shapes cancer evolution and the role of immunoediting in CPI failure. This analysis will be made possible by the TRACERx, PEACE studies and the DARWIN II clinical trial, managed by the host lab. I will integrate different data, including 500X whole-exome sequencing, Imaging Mass Cytometry, evolutionary reconstruction and detailed clinical annotation, to do an unprecedented analysis of the spatial and temporal heterogeneity of immunoediting mechanisms, and how they relate to features of the cancer genome, transcriptome, tumour microenvironment and CPI responses.
Organisations
People |
ORCID iD |
| Oriol Pich I Rosello (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
Bailey C
(2024)
Origins and impact of extrachromosomal DNA.
in Nature
Biswas D
(2025)
Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.
in Nature cancer
Castignani C
(2024)
Abstract 2268: CREDAC: Copy number-based reference-free expression deconvolution analysis of cancers
in Cancer Research
Caswell DR
(2024)
The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
in Nature genetics
Dietzen M
(2022)
Abstract 3620: Investigating the role of altered replication timing during tumor evolution in lung and breast cancer
in Cancer Research
Frankell AM
(2023)
The evolution of lung cancer and impact of subclonal selection in TRACERx.
in Nature
Hessey S
(2023)
Abstract 2037: Tracking the emergence of immunotherapy resistance in lung cancer metastases
in Cancer Research
Hiley C
(2022)
Abstract 645: Heterogeneity of immunotherapy biomarkers in the TRACERx non-small cell lung cancer multi-region lung cancer cohort study
in Cancer Research
Hill W
(2023)
Lung adenocarcinoma promotion by air pollutants.
in Nature
Huebner A
(2022)
Abstract 3792: TRACERx: Mapping the evolution of metastases in non-small cell lung cancer
in Cancer Research
Hynds R
(2022)
3MO Genomic evolution of non-small cell lung cancer during the establishment and propagation of patient-derived xenograft models
in Annals of Oncology
Hynds RE
(2024)
Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.
in Nature communications
Karasaki T
(2023)
Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
in Nature medicine
Lange JT
(2022)
The evolutionary dynamics of extrachromosomal DNA in human cancers.
in Nature genetics
Lu WT
(2025)
TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
in Nature cell biology
Ng KW
(2023)
Antibodies against endogenous retroviruses promote lung cancer immunotherapy.
in Nature
Pich O
(2022)
The translational challenges of precision oncology.
in Cancer cell
Usaite I
(2023)
Quantifying the impact of immunotherapy on RNA dynamics in cancer.
in Journal for immunotherapy of cancer
Zhai H
(2022)
Abstract 3626: Genomic evolutionary patterns in matched pre-invasive and invasive lung disease in TRACERx
in Cancer Research
| Description | By integrating data from multiple lung-cancer cohorts, together with cohorts where normal lung has been sequenced, we have seen the relationship between certain genomic alterations in the tumours and their impact on the surrounding cells (the microenvironment). For example, tumours from patients that never smoked tend to have a distinct microenvironment compared to those arising from patients that smoke or have smoked in the past. We are currently investigating how this influences the genomic make-up of the tumour (eg, whether the immune system deletes clones harbouring certain mutations that can generate strong immune responses). The TRACERx and PEACE data also allows us to infer how much these states are heterogeneous within the same tumour - we are observing certain types of microenvironments that tend to cooccur in the same patient more than expected. Finally, the TRACERx data also allow us to study these changes across tumour evolution. For example, we observed how cisplatin, a common treatment in lung cancer, diminishes the amount of T cells (a type of immune cell). All these and other findings will be published in a peer reviewed journal. Besides the scientific output of this work, we are also providing a framework to integrate both clinical, DNAseq and RNAseq using state-of-the-art methods that can be leveraged to study other tumour types, such as breast cancer or colorectal cancer. In summary, the integration of several cohorts, including TRACERx, offers an unprecedented opportunity to study lung cancer evolution. One of the most important outcomes of this research will also be sharing the data with the scientific community so that further advances can be made upon our research. |
| Exploitation Route | Our research opens the door to future endeavours related to cancer evolution in the context of certain microenvironments in other tumour types. Our generated dataset will also help lung cancer researchers as it is to the best of our knowledge the biggest cohort of lung cancer data uniformly processed to date. |
| Sectors | Healthcare |
| Description | A Question of Science Podcast with Brian Cox - BBC Studios Production |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2025 |
| Description | Article: Evolving our understanding of cancer: an interview with Charles Swanton |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2025 |
| Description | Cell Press - 50 inspiring scientists - Oncologist Charles Swanton believes innovation in science is about improving lives |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2024 |
| Description | Naked Scientist podcast: Latest developments in our understanding of cancer mechanisms are shaping treatments and preventative measures - Host: Chris Smith |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2025 |
| Description | Naked Scientists podcast - Why the immune system holds the key to cancer treatment |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2024 |
| Description | The Naked Scientists podcast: Lung cancer looking at the latest developments (23 Sept 2025) |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | NA |
| Year(s) Of Engagement Activity | 2025 |