Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers
Abstract
Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/DDX58) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell–intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment in vivo.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 01, 2018
- Source ID
- 10.1158/0008-5472.can-18-0730
Entities
People
- Anna Marie Pyle
- Bushra Rahman
- David L. Elion
- Donna J. Hicks
- John T Wilson
- Max E. Jacobson
- Olga Fedorova
- Paula González Ericsson
- Rebecca S. Cook
- Violeta Sanchez
Organizations
- Congressionally Directed Medical Research Programs
- National Center for Advancing Translational Sciences
- National Institutes of Health
- Vanderbilt University
- Yale University