Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models

Abstract

Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor’s sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death–associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that 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, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.

Sonosensitizer nanoplatform-mediated sonodynamic therapy induced immunogenic cell death and tumor immune microenvironment variation

“…Photothermal therapy and sonodynamic therapy have been demonstrated to boost lymphocyte infiltration and augment the antitumor effects of ICIs (Liang et al., 2019 ; Zhang et al., 2020 ; Si et al., 2021 ) reported that pure oxygen-carrying NPs triggered by US also have the ability to activate antitumor immunity in the body. Combining nanomedicine with immunotherapy is an important method to improve therapeutic effects (Ye et al., 2019 ; Lin et al., 2021 ). Our study showed that IRO@FA NP-mediated SDT induced the infiltration of CD3 + T and CD8 + T cells.…”

RNA-mediated immunotherapy regulating tumor immune microenvironment: next wave of cancer therapeutics

“…PTEN reactivation leads to autophagy, which triggers the release of damage-associated molecular patterns. These molecules reverse the immunosuppressive TME and induce cell death in cancer by enhancing CD8 + T cell infiltration and reduction of Tregs and MDSCs [ 47 ]. Therefore, advanced protocols for the transport of tumor suppressors provide an opportunity to improve antitumor immune responses in the TIME [ 47 ].…”

“…These molecules reverse the immunosuppressive TME and induce cell death in cancer by enhancing CD8 + T cell infiltration and reduction of Tregs and MDSCs [ 47 ]. Therefore, advanced protocols for the transport of tumor suppressors provide an opportunity to improve antitumor immune responses in the TIME [ 47 ]. The major challenge of using mRNA-based treatments are their instability and easy degradability by ribonucleases.…”

Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy

“…Nanotechnology can also be used to transport mRNA or siRNA to a specific cell population in a targeted manner ( 184 , 185 ). For example, NPs carrying PTEN mRNA were effectively delivered to PTEN null cancer cells, and restoration of PTEN expression induced immunogenic death of cancer cells and thus induced potent antitumor immune responses in melanoma tumor-bearing mice ( 186 ). In summary, by combining nanotechnology and a variety of approaches, TAMs can be modified in a targeted manner, and their anticancer activities can be promoted.…”