Transforming the Tumour Microenvironment
One of the significant challenges in the fight against cancer extends beyond the mere destruction of tumour cells; it involves enabling the immune system to recognise and combat them effectively. In numerous cases, a tumour’s microenvironment presents obstacles that inadvertently support cancer progression. Researchers from the University of Adelaide in Australia have made strides in this area by developing intelligent nanoparticles capable of directly intervening in this environment, effectively turning certain immune cells into allies in the fight against tumours.
The recently published study in Science Advances focuses on tumour-associated macrophages, which are immune cells that can exhibit contradictory roles. Although macrophages typically serve as defenders of the body, within certain tumours, they may adopt immunosuppressive behaviours, contributing to an environment that hinders the activity of T lymphocytes—one of the primary weapons in the immune system’s arsenal against cancer cells.
Chunxia Zhao, the principal investigator and a professor at the School of Chemical Engineering, explained, “One of the greatest challenges in cancer immunotherapy is that while the immune system has the capacity to attack a tumour, the tumour microenvironment can prevent these immune cells from fulfilling their roles.” She further elucidated that their innovative approach aims to modify the microenvironment from within the tumour itself. By specifically targeting tumour-associated macrophages, the treatment can be delivered precisely where it is needed, stimulating T cells to penetrate and activate within the tumour.
Mechanisms Behind the Intelligent Nanoparticles
The strategy employed by the researchers involves the use of lipid nanoparticles—tiny structures designed to transport molecules into cells. These nanoparticles carry two key components: a molecule known as resiquimod, which stimulates specific immune pathways, and messenger RNA (mRNA) that contains instructions for producing CXCL9, a chemokine that signals the recruitment of cytotoxic T lymphocytes (CD8+), which are specialised in destroying abnormal cells.
Crucially, the effectiveness of this system lies in its targeting mechanism. The nanoparticles were coated with antibodies that specifically bind to TREM2, a protein found on immunosuppressive tumour-associated macrophages. This design ensures that the treatment preferentially reaches these macrophages rather than the cancer cells themselves. Laboratory experiments demonstrated that this targeting approach enhanced mRNA delivery to the immunosuppressive macrophages while simultaneously reducing delivery to the tumour cells.
Once internalised by the macrophages, the treatment aimed to achieve a dual effect. Resiquimod worked to reprogramme these cells, diminishing their immunosuppressive behaviour. Concurrently, the mRNA enabled the macrophages to produce CXCL9, the chemical signal that facilitates T lymphocyte infiltration into the tumour.
In Vivo Results and Future Implications
In vitro results revealed that TREM2-targeted nanoparticles significantly increased CXCL9 production and decreased the expression of ARG1—an immunosuppressive marker—by 2.5 times. Simultaneously, they enhanced the expression of NOS2, which is associated with a more inflammatory profile, by an impressive 89.5 times.
The next step for the researchers was to assess whether this mechanism would be effective within a living organism. They administered the treatment to mice with 4T1 breast tumours. Following three doses, they observed a marked reduction in tumour growth accompanied by a significant increase in CXCL9 levels within the tumours. In the group treated with TREM2-targeted nanoparticles, the concentration of this chemokine was approximately four times higher than that observed in the control group.
Additionally, the treatment led to a 63.2% reduction in the proportion of immunosuppressive macrophages within the tumours, while simultaneously increasing the presence and activity of cytotoxic T lymphocytes, the cells responsible for attacking cancer cells directly.
Combination Therapies and Safety Assessments
The researchers also explored the potential of combining their approach with existing immunotherapies that target immune checkpoint inhibitors: PD-L1 and CTLA-4. While this combination did not result in a significant additional reduction in tumour size in this model, it did induce notable changes within the immune system. There was an increase in both helper T lymphocytes and cytotoxic T lymphocytes within the tumours, as well as an increase in central memory T cells in the lymph nodes draining the tumour, which is associated with a potentially more durable immune response.
The study also evaluated potential adverse effects on organs such as the liver, lungs, spleen, and kidneys. The researchers noted a generally favourable tolerance and did not observe significant morphological changes, aside from some alterations linked to immune system activation. However, they caution that further investigation into systemic inflammation and long-term toxicity is essential before considering clinical trials.
Professor Zhao remarked, “This is an important proof of concept demonstrating that we can use mRNA and nanoparticle technology to reprogramme the immune microenvironment of a tumour. While much work remains before this approach could be considered for patients, these results provide a promising foundation for the development of new cancer immunotherapies.”
The comprehensive study can be accessed and downloaded for further insights.