CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection
Open Access
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 8 (4), 465-478
- https://doi.org/10.1158/2326-6066.CIR-19-0449
Abstract
The ability of focal radiotherapy to promote priming of tumor-specific CD8(+) T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of cytotoxic T-lymphocyte-associated protein 4 blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy.Other Versions
Funding Information
- U.S. Department of Defense (W81XWH-17-1-0029)
- Multi-Team Award (W81XWH-11-1-0530)
- NIH (R01 CA201246)
- Breast Cancer Research Foundation (BCRF-16-054, BCRF-17-053)
This publication has 50 references indexed in Scilit:
- ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapyOncoImmunology, 2013
- Type I interferon is selectively required by dendritic cells for immune rejection of tumorsThe Journal of Experimental Medicine, 2011
- The Efficacy of Radiotherapy Relies upon Induction of Type I Interferon–Dependent Innate and Adaptive ImmunityCancer Research, 2011
- CD73 on Tumor Cells Impairs Antitumor T-Cell Responses: A Novel Mechanism of Tumor-Induced Immune SuppressionCancer Research, 2010
- Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer ImmunityCancer Research, 2010
- Batf3 Deficiency Reveals a Critical Role for CD8α + Dendritic Cells in Cytotoxic T Cell ImmunityScience, 2008
- Adenosine receptors in regulation of dendritic cell differentiation and functionBlood, 2008
- A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cellsBlood, 2008
- A2A adenosine receptor protects tumors from antitumor T cellsProceedings of the National Academy of Sciences of the United States of America, 2006
- CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cellsJCI Insight, 2006