Recently, a research team led by Prof. WANG Hao from the National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences (CAS), collaborating with Profs. Omid C. Farokhzad and SHI Jinjun from Harvard Medical School, as well as MEI Lin from Sun Yat-Sen University, reported a novel anti-tumor strategy by combing with mRNA drugs and tumor immunotherapy. This work was published in Science Translational Medicine, and selected as the cover article.
Recent clinical studies have shown that PTEN mutation or loss is markedly associated with reduced T cell infiltration at tumor sites and poor response or resistance to PD-1 blockade therapy. The loss of PTEN may contribute to the accumulation of suppressive immune cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells, as well as the formation of an immunosuppressive microenvironment (TME) during tumor initiation and progression. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor’s sensitivity to immune checkpoint blockade (ICB) therapy.
To address this issue, the research team developed a novel nanomedicine by combining mRNA and nanotechnology, which can efficiently deliver exogenous PTEN mRNA to the tumor site and successfully restore the tumor suppressor function of PTEN, and induce tumor cells immunogenic death. This mRNA nanomedicine has also shown excellent therapeutic effects and good safety in different tumor models (melanoma xenograft tumor, prostate tumor orthotopic model and transgenic mouse model). PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti-programmed death 1 antibody, exhibits an improved anti-tumor immunotherapy effect in preclinical models.
This study provides a robust and potent strategy for eliciting anti-tumor immune responses that may be useful against different cancer types possessing PTEN loss or mutation, and scientists expect that the combination of mRNA nanomedicine with ICB therapy could lead to development of tumor suppressor pathway-specific precision immunotherapy for effective and safe cancer treatment.
Figure: Preclinical study on the combination therapy of novel PTEN mRNA nanomedicine and immune checkpoint inhibitor
National Center for Nanoscience and Technology