2024-08-28 マサチューセッツ大学アマースト校
<関連情報>
- https://www.umass.edu/news/article/new-pancreatic-cancer-treatment-proves-effective-shrinking-clearing-tumors
- https://www.science.org/doi/10.1126/scitranslmed.adj9366
自然免疫アゴニストと老化誘導剤を組み合わせたナノ粒子送達が膵臓癌のT細胞制御を促進する Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer
Loretah Chibaya, Kelly D. DeMarco, Christina F. Lusi, Griffin I. Kane, […], and Marcus Ruscetti
Science Translational Medicine Published:28 Aug 2024
DOI:https://doi.org/10.1126/scitranslmed.adj9366
Editor’s summary
Unlike other tumor types, existing immunotherapies have not proven very successful for pancreatic ductal adenocarcinoma (PDAC), necessitating the development of additional approaches. Here, Chibaya et al. developed a combination therapy approach that included nanoparticle delivery of STING and TLR4 agonists, which stimulate the immune response, in combination with the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib, which promote senescence of tumor cells. The combination therapy induced robust antitumor immune responses that controlled tumor burden in implanted and autochthonous PDAC mouse models. These data support further development of this potent combination therapy for PDAC. —Courtney Malo
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which 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 proinflammatory signaling pathways, 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–mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon–driven innate and adaptive immune response with durable antitumor efficacy against PDAC.
