2. Academic Validation
  3. Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer

Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer

  • bioRxiv. 2023 Sep 18:2023.09.18.558307. doi: 10.1101/2023.09.18.558307.
Loretah Chibaya 1,  Christina F Lusi 2,  Kelly D DeMarco 1,  Griffin I Kane 2,  Meghan L Brassil 2,  Chaitanya N Parikh 1,  Katherine C Murphy 1,  Junhui Li 1,  Tiana E Naylor 2,  Julia Cerrutti 2,  Jessica Peura 1 3,  Jason R Pitarresi 1 3,  Lihua Julie Zhu 1 4 5,  Katherine A Fitzgerald 6,  Prabhani U Atukorale 2 6 7,  Marcus Ruscetti 1 7 8
Affiliations

Affiliations

  • 1 Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 2 Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA USA.
  • 3 Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 4 Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 5 Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 6 Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 7 Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA. USA.
  • 8 Immunology and Microbiology Program, University of Massachusetts Chan Medical School, Worcester, MA, USA.
PMID: 37790484 DOI: 10.1101/2023.09.18.558307
Abstract

Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and Other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.

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