Adelaide University researchers have developed a new way of using mRNA technology to reprogram tumour-supporting immune cells and strengthen the body's anti-cancer immune response.
The scientific team, spanning engineering, biomedical, oncology and immunology experts, has developed tiny, targeted particles that could help the immune system fight cancer by reprogramming immune cells within the tumour environment.
The findings have been published in Science Advances today.
The new approach uses lipid nanoparticles – the same delivery technology used to deliver mRNA in COVID-19 vaccines – to target a type of immune cell that can help tumours evade the body's defences.
In animal experiments, the nanoparticles were designed to find tumour-associated macrophages, or TAMs, which are large, white blood immune cells commonly found in tumours.
Rather than attacking these cells, the researchers effectively reprogrammed them so they became less suppressive and helped attract cancer-fighting T cells into the tumour.
Lead researcher Professor Chunxia Zhao from Adelaide University's School of Chemical Engineering said the research tackles a major challenge in cancer immunotherapy – getting immune cells into tumours and keeping them active.
"One of the biggest challenges in cancer immunotherapy is that the immune system may be capable of attacking a tumour, but the tumour environment can stop those immune cells from doing their job," Professor Zhao said.
"Our approach is designed to change that environment from within the tumour. By specifically targeting tumour-associated macrophages, we can deliver the treatment where it is needed and encourage the immune system's cancer-fighting T cells to enter the tumour and become more active."
The nanoparticles were coated with an antibody that recognises a protein called TREM2, which is highly expressed on the tumour-associated macrophages.
Once inside the macrophages, the particles delivered two key ingredients: an mRNA molecule carrying instructions to produce a chemical signal called CXCL9, and a compound called Resiquimod that helps switch the macrophages away from their immune-suppressing behaviour.
CXCL9 acts like a chemical beacon, helping attract cancer-fighting CD8+ T cells into the tumour.
In mouse experiments, treatment reduced the proportion of immune-suppressing macrophages by more than 60% and increased CXCL9 levels in tumours fourfold. The researchers also observed greater numbers and activity of cancer-fighting T cells and a moderate reduction in tumour growth.
When the treatment was combined with existing immune checkpoint-blocking drugs targeting PD-L1 and CTLA-4, the researchers saw further increases in cancer-fighting T cells and the development of central memory T cells, which could help the immune system remember and respond to cancer in the future. However, the combination did not produce additional tumour-growth inhibition in this particular mouse model.
Professor Zhao said the findings could open a new avenue for improving immunotherapy for solid cancers, where the tumour environment can prevent immune treatments from working effectively.
"This is an important proof of concept that we can use mRNA and nanoparticle technology to reprogramme the immune environment of a tumour.
"There is still significant work to do before this approach could be considered for patients, but these results provide an encouraging foundation for developing more targeted cancer immunotherapies."
The research was led by Adelaide University researchers in collaboration with SA Pathology and the Royal Adelaide Hospital.
'Targeting tumor-associated macrophages using mRNA lipid nanoparticles for cytotoxic T lymphocyte–mediated cancer immunotherapy' is published in Science Advances. DOI: 10.1126/sciadv.aed9568
