Accession Number:

AD1105418

Title:

Adenosine Blockade with Radiotherapy to Enhance Responses of Breast Cancer to Immune Checkpoint Inhibitors

Descriptive Note:

Technical Report,01 Feb 2017,31 Jan 2020

Corporate Author:

Weill Cornell Medicine New York United States

Personal Author(s):

Report Date:

2020-05-01

Pagination or Media Count:

50.0

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.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE