Research ArticleCancer

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

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Science Translational Medicine  23 Jun 2021:
Vol. 13, Issue 599, eaba9772
DOI: 10.1126/scitranslmed.aba9772

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Promoting PTEN

A mechanism by which tumors promote an immune suppressive microenviroment is through deletion or mutation of tumor suppressor genes, including the gene encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Thus, restoration of PTEN expression in tumor cells may serve as a means of enhancing antitumor immunity. To accomplish this, Lin et al. delivered PTEN-encoding synthetic mRNA in nanoparticles in vitro and in vivo. The nanoparticle-delivered mRNA led to expression of PTEN in tumor cells, which in turn reversed the suppressive tumor microenvironment. This led to improved control of tumor burden in mouse models of melanoma and prostate cancer. Thus, delivery of tumor suppressor–encoding mRNAs by nanoparticles may be a strategy to improve antitumor immune responses.

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.

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