Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction

Details

• Personal Author:
  Baljon JJ ; Bennett NE ; Fischer MA ; Florian DC ; Guelcher SA ; Merkel AR ; Odziomek M ; Rhoades JA ; Savona MR ; Wehbe M ; Wilson JT
• Description:
  When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 hours, enhancing antitumor immunity through proinflammatory cytokine production and early T-cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after 2 weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction. Significance: Bone metastases are difficult to treat due to the inaccessibility of the bone marrow compartment and the immunosuppressive microenvironment that protects resident stem cells. Packaging a STING agonist into a nanoparticle that enables systemic administration and drug accumulation at tumor sites overcomes both barriers to stymie metastatic breast cancer growth. [Description provided by NIOSH]
• Subjects:
  Immune System Occupational Health Safety
• Keywords:
  Bone Disorders Bone Marrow Breast Cancer Immune Reaction Metastatic Disease Nanoparticles Tumor Inhibition
• ISSN:
  2767-9764
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2 ; OSHA Region 4 ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  223-234
• Volume:
  3
• Issue:
  2
• NIOSHTIC Number:
  nn:20068543
• Citation:
  Cancer Res Commun 2023 Feb; 3(2):223-234
• Contact Point Address:
  John T. Wilson, Vanderbilt University, Nashville, TN 37212
• Email:
  john.t.wilson@vanderbilt.edu
• Federal Fiscal Year:
  2023
• Performing Organization:
  Albert Einstein College of Medicine, Bronx, New York
• Peer Reviewed:
  True
• Start Date:
  20210701
• Source Full Name:
  Cancer Research Communications
• End Date:
  20240630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e69ff557e66e8b88c23b40adf64f55c33681722263e549c98ba539dd8768c0ba57e7662ddf796b149c2c2e5b89f37273a991b9ff88a78b076339d72e824c9c01
• Download URL:
  https://stacks.cdc.gov/view/cdc/207154/cdc_207154_DS1.pdf
• File Type:
  [PDF - 13.60 MB ]