Inside-Out Immunotherapy: Preventing Metastatic Breast Cancer Recurrence via Nanoparticle-Directed Modulation of the Tumor Microenvironment
Abstract
Purpose. We proposed to design and validate immunotherapeutic nanoparticles (IT-NPs) for precise immunomodulation of the tumor microenvironment. Our hypothesis is that that activation of RIG-I in combination with intra-tumoral silencing of TGF-beta receptor 2 will induce systemic antitumor immunity for eradicating local disease, distant disease, and future recurrences. Scope: We proposed to (1) develop IT-NPs for intra-tumoral delivery breast tumors (led by Initiating PI Wilson); (2) evaluate the effect of local RIG-I activation in breast cancer cells and in the breast TME in immunocompetent mice (led by Partnering PI Cook); and (3) demonstrate that IT-NPs induce breast tumor regression, eliminate metastatic tumors, and prevent future metastatic recurrence using mouse breast cancer models (Wilson and Cook together). Major Findings: 1.) The RIG-1 mimetic (5ppp-HP20) potently activates Type I inflammatory cytokines in human and mouse breast cancer cells; 2.) The RIG-1 mimetic fails to induce inflammation in breast cancer cells with genomic loss of DDX58, the gene encoding RIG-1. 3.)The RIG-I mimetic induces pyroptotic cell death in breast cancer cells; 4.) Intra-tumoral IT-NP delivery of RIG-I mimetic decreased growth and metastasis of breast cancers in immune-competent mice. Significance. 1.) RIG-I mimetic induced inflammatory cytokines and pyroptosis (an immunogenic cell death), which will maximize antitumor immune responses while reducing tumor cell burden directly. 2.) Tumor DDX58 can be used to predict response (or lack of response) to RIG-I mimetics.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2020
- Accession Number
- AD1124259
Entities
People
- Craig Duvall
- John T Wilson
- Rebecca S. Cook
Organizations
- Vanderbilt University