Treatment combinations key to tackling cancer
The last decade has seen significant advances in the development of cancer immunotherapies. These are treatments that use the immune system to fight disease. “Immunotherapies have completely transformed cancer treatment,” notes TxImmuneOrganoids project leader Krijn Dijkstra from the Netherlands Cancer Institute. “This is fantastic for patients, and has also opened up a whole new research field.”
Understanding tumour responses to immunotherapies
At the same time however, while immunotherapies can be effective at shrinking tumour size, complete eradication of cancer cells remains a challenge. One reason for this is that tumours are not homogeneous. While some tumour cells might be susceptible to therapy, other cells are resistant. “If the tumour is not completely eradicated, then it might start to grow again at some point,” says Dijkstra. “This will require the development of new therapies.” The TxImmuneOrganoids project, which was supported by the Marie Skłodowska-Curie Actions programme, set out to better understand tumour responses to immunotherapies. The project focused on lung cancer, and was coordinated by Charles Swanton, a leading expert in tumour heterogeneity at the Francis Crick Institute in the United Kingdom.
Analysing cells from individual tumours
As a tumour grows, it starts branching off into subclones. Dijkstra wanted to know whether these clones are not only genetically but also functionally distinct, and whether these differences might be the reason some cells are targeted by immune cells, and others are not. To do this, Dijkstra and his team developed a range of organoids, to see how specific tumour cells might respond to the introduction of T-cells – a type of white blood cell that helps the immune system fight disease. Organoids are miniature, simplified versions of living tissue created in the lab, which mimic key structural and biological features found in the body. “To develop the organoids, we took biopsies from different regions of a patient tumour,” says Dijkstra. “We created around 25 organoid cultures from the same tumour. In this way, we were able to break the tumour down, and test each individual component separately.” Through this groundbreaking technique, Dijkstra was able to demonstrate that individual cancer cells from the same tumour indeed respond differently to the introduction of T-cells. “It was sometimes like night and day,” he remarks. By measuring the degree of T-cell activation, Dijkstra was able to calculate how effective certain T-cells are in targeting specific cancer cells. This could help in identifying effective new immunotherapy treatments.
Combinations of cancer therapies
The project has underlined that a tumour is fundamentally a mosaic of individual cells, which tend to be genetically and functionally distinct. This underlines why treating cancer with a single therapy is such a challenge – only some cancer cells will be predisposed to be responsive. These findings are in keeping with the general direction of cutting-edge cancer research, which is towards the development of combinations of therapies. “Moving forward, I’d be really interested to know why it is that tumours are so heterogenous,” adds Dijkstra. “Is this just a chance, natural side effect of how tumours evolve? Or do tumour cells work as a team, with some keeping immune cells at bay, and others performing other functions? This is something I’d like to follow up on.”
Keywords
TxImmuneOrganoids, cancer, immune, tumour, immunotherapies, disease
