The same technology used to deliver mRNA in COVID-19 vaccines is being used to target a type of immune cell that can help tumors evade the body’s defenses.
RT’s Three Key Takeaways:
- Reprogramming Tumor Defenses: Adelaide University researchers engineered targeted lipid nanoparticles to reprogram immunosuppressive tumor-associated macrophages rather than destroying them, according to a study published in Science Advances.
- Enhanced T-Cell Infiltration: In preclinical animal models, the targeted particles reduced suppressive macrophages by more than 60% and increased chemical signals that attract cancer-fighting CD8+ T cells into tumors fourfold.
- Combination Therapy Potential: Combining the nanoparticle platform with checkpoint inhibitor therapies promoted the development of central memory T cells, offering a foundation for future solid tumor immunotherapies.
Adelaide University researchers have developed a method using messenger RNA (mRNA) technology to reprogram tumor-supporting immune cells and strengthen the body’s anti-cancer immune response, according to findings published in Science Advances.
The collaborative team, spanning engineering, biomedical, oncology, and immunology experts, developed targeted lipid nanoparticles designed to alter immune cells directly within the solid tumor microenvironment. The delivery platform adapts the lipid nanoparticle technology used in COVID-19 vaccines to target tumor-associated macrophages (TAMs), large white blood cells that frequently suppress anti-tumor activity and assist tumors in evading host defenses.
Rather than depleting or destroying these immune cells, the nanoparticles reprogram them so they become less suppressive and actively recruit cancer-fighting T cells into the tumor mass.
“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,” said Chunxia Zhao, lead researcher and professor at Adelaide University’s School of Chemical Engineering. “Our approach is designed to change that environment from within the tumour. By specifically targeting tumor-associated macrophages, we can deliver the treatment where it is needed and encourage the immune system’s cancer-fighting T cells to enter the tumor and become more active.”
Targeted Delivery Mechanism
To ensure precise cellular uptake, the researchers coated the nanoparticles with an antibody that binds to triggering receptor expressed on myeloid cells 2 (TREM2), a surface protein highly expressed on TAMs, according to the study.
Once inside the targeted macrophages, the particles release two therapeutic components: an mRNA molecule encoding instructions to produce the chemokine CXCL9, and a compound called Resiquimod. Resiquimod prompts the macrophages to switch away from their immune-suppressing state, while CXCL9 functions as a chemical beacon to draw cancer-fighting CD8+ T cells into the core of the tumor.
Preclinical Results and Next Steps
In animal models, treatment with the nanoparticles reduced the proportion of immune-suppressing macrophages by more than 60% and increased CXCL9 levels within tumors fourfold, the study reported. The investigators observed greater infiltration and functional activity among cancer-fighting T cells, resulting in a moderate reduction in tumor growth.
The researchers also paired the nanoparticle system with immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). While the combination generated further increases in cancer-fighting T cells and stimulated central memory T cells—which may aid long-term immune surveillance—it did not yield additional tumor-growth inhibition in the evaluated mouse model.
“This is an important proof of concept that we can use mRNA and nanoparticle technology to reprogram the immune environment of a tumor,” said Zhao, lead researcher. “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.”
