Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth in Vivo

Zeinab Y. Al Subeh, Dakota B. Poschel, Priscilla S. Redd, John D. Klement, Alyssa D. Merting, Dafeng Yang, Megh Mehta, Huidong Shi, Yolonda L. Colson, Nicholas H. Oberlies, Cedric J. Pearce, Aaron H. Colby, Mark W. Grinstaff, Kebin Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells. Emerging clinical and experimental data indicate that Fas is essential for the efficacy of CAR-T cell immunotherapy. Furthermore, loss of Fas expression is a hallmark of human melanoma. We hypothesize that restoring Fas expression in tumor cells reverses human melanoma resistance to T cell cytotoxicity. DNA hypermethylation, at the FAS promoter, down-regulates FAS expression and confers melanoma cell resistance to FasL-induced cell death. Forced expression of Fas in tumor cells overcomes melanoma resistance to FasL-induced cell death in vitro. Lipid nanoparticle-encapsulated mouse Fas-encoding plasmid therapy eliminates Fas+ tumor cells and suppresses established melanoma growth in immune-competent syngeneic mice. Similarly, lipid nanoparticle-encapsulated human FAS-encoding plasmid (hCOFAS01) therapy significantly increases Fas protein levels on tumor cells of human melanoma patient-derived xenograft (PDX) and suppresses the established human melanoma PDX growth in humanized NSG mice. In human melanoma patients, FasL is expressed in activated and exhausted T cells, Fas mRNA level positively correlates with melanoma patient survival, and nivolumab immunotherapy increases FAS expression in tumor cells. Our data demonstrate that hCOFAS01 is an effective immunotherapeutic agent for human melanoma therapy with dual efficacy in increasing tumor cell FAS expression and in enhancing CTL tumor infiltration.

Original languageEnglish (US)
Pages (from-to)12695-12710
Number of pages16
JournalACS Nano
Volume16
Issue number8
DOIs
StatePublished - Aug 23 2022
Externally publishedYes

Keywords

  • CTL tumor infiltration
  • DNA liposome therapy
  • Fas
  • FasL DNA hypermethylation
  • humanized NSG mice
  • lipid nanoparticle
  • melanoma PDX

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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