Adenosine Blockade with Radiotherapy to Enhance Responses of Breast Cancer to Immune Checkpoint Inhibitors
Technical Report,01 Feb 2017,31 Jan 2020
Weill Cornell Medicine New York United States
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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.
- Medicine and Medical Research