Adenosine Blockade with Radiotherapy to Enhance Responses of Breast Cancer to Immune Checkpoint Inhibitors
Abstract
A majority of patients with advanced breast cancer are currently non-responsive to immune checkpoint blockade (ICB) due to a lack of intratumoral CD8 T cell infiltration. Localized radiation therapy (RT) can be used as a spark to trigger systemic immunity and render patients susceptible to ICB, mediating abscopal effects (outside of the irradiated field) and occasionally tumor clearance and long-lasting immune memory. The ability of the host to mount tumor-specific CD8 T cell responses is highly dependent on tumor infiltration of dendritic cells (DCs), particularly conventional type I DCs (cDC1). However, following RT, adenosine (ADO) accumulation in the tumor microenvironment (TME) acts to suppress both DC subsets and effector CD8 T cells thus limiting the immunogenic effect of RT. During the research project, we have described that high doses of RT induces a rapid increase in ADO levels in tumors and causes upregulation of key enzymes involved in generation of ADO on tumor cells. Moreover, we have shown that ADO-blockade by anti-CD73 antibody therapy promotes infiltration of cDC1 cells in irradiated tumors. Importantly, we demonstrate that ADO-blockade promotes synergy between RT and ICB to induce systemic immune responses in mouse models of metastatic breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2020
- Accession Number
- AD1105418
Entities
People
- Erik Wennerberg
Organizations
- Weill Cornell Medicine