Nature published a collection of papers reporting the TRACERx study. It was set up in 2014 to study cancer dynamics and immune system changes during development of lung cancer.
High-level outcome of the study
The studies published so far share the results of analysing the first 100 samples of the cohort.
A comment article by the chief scientist leading the project, Charles Swanton, summarized main outcomes of the project:
- Whole genome duplications are common in lung cancer tumours. Point mutations are also common. They are caused by tobacco exposure and the activity of cytidine deaminases, which deactivate invading viruses as part of the immune response.
- Among smokers, whole genome duplications take place early. Mutations associated with smoking dominate the trunk of the tumour’s evolutionary tree. They are called founder mutations or truncal mutations, which means that they are likely present in most tumour cells.
- DNA sequences of T-cell receptors evolved parallel with the tumour. The tumor eventually adapts to its immune environment and avoids destruction. A possible explanation is that the chromosomal instability of tumour cells cause them to lose immune-recognition molecules known as human leukocyte antigen (HLA) on their surface, which prevents T cells from homing in on the tumour.
For clinicians, the study reveals potential benefit of computer tomography (CT) screening (reduction of mortality rate from 3.3 deaths per 1,000 person-years to 2.5 deaths). Personalized treatment may improve prognosis, for instance, some patients (5-15 out of 100) will benefit from chemotherapy after surgery. Currently, though, we cannot predict who benefit from it most. Detection of circulating free DNA that contains founder (truncal) mutations may be used to identify this sub-population, based on the hypothesis that chemotherapy benefits patients with tumour DNA in their blood after surgery most.
From the drug discovery perspective, it may be necessary to target multiple cancer proteins carrying founder mutations at the same time with immunotherapies.
A skewed distribution of CD4 and CD8 T cells in lung cancer
Colleagues interested in T cells may find the following publication interesting, which use material from the TRACERx cohort. Ghorani et al. share on Nature Cancer a comprehensive characterization of CD4 (including immature and mature helper T cells) and CD8 (including immature and mature cytotoxic T cells) in non-small cell lung cancer, using flow cytometry, exome sequencing, single-cell sequencing, and bulk sequencing.
They show that tumour mutation burden was associated with changes T cell differentiation and composition, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD4 and CD8 T cells that resemble neoantigen-recative CD8 T cells. The shift of distribution was associated with poor survival in lung and other cancer cohorts with gene signature analysis.
Understanding the diseases dynamics and the co-evolution of both disease and the immune system is a fascinating topic. I think it remains a challenge to identify from the many different types of changes that we observe the causal nodes or links of interaction networks that we can target as drug targets, and show that the therapeutics are efficacious and safe.
Studies like TRACERx defnitely enriches our knowledge in this aspect. Now it is the turn of the community, including biopharmaceutical companies, to turn the knowledge and insight into drugs and therapeutics. The founder mutations, for instance, seem to be particularly interesting. What happens if we remove cells harbouring them? Will other mutations appear that escape immunotherapy? I am excited to see the progress in this field.
More broadly, I wish we as a community have more resources like TRACERx for other diseases, especially neurodegenerative diseases, infectious diseases, and autoimmune diseases. I believe patient-specific and targeted therapeutics can be made by understanding how the immune system co-evolute with the disease, especially when part of it is causing the disease.