Mechanisms of Resistance to Immunotherapy in Osteosarcoma
Abstract
Osteosarcoma is a cancer that primarily affects children, adolescents, and young adults. Sofar, treatment of this cancer with immunotherapy has been unrewarding. However, themechanisms that mediate resistance to immunotherapy are poorly understood. Our goal is todetermine whether osteosarcoma-derived exosomal microRNAs inactivate immune cells in or nearthe tumor environment. We have found that CD28 might be a target through which osteosarcomasrestrain T cell activation, although different mechanisms might mediate this effect in tumorsfrom humans and from dogs. Overall, the transcriptional programs in osteosarcoma, includingthose of immune cells in the microenvironment, are controlled by epigenetic mechanisms thatinclude chromatin modification (methylation) and microRNA-dependent RNA degradation. A majorinnovation from our work is the development of a novel molecule that simultaneously inhibitsmyeloid and exhaustion immune checkpoints, and which may have the capacity to mitigateosteosarcoma-mediated immunosuppression. This approach could change the paradigm of howimmunotherapy is used for this and other solid tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1128351
Entities
People
- Jaime F. Modiano
Organizations
- University of Minnesota