Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
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Open Access
- 2 January 2014
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 124 (2), 687-695
- https://doi.org/10.1172/jci67313
Abstract
High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death–ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti–PD-L1 enhanced the efficacy of IR through a cytotoxic T cell–dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti–PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.Keywords
This publication has 44 references indexed in Scilit:
- A CXCL1 Paracrine Network Links Cancer Chemoresistance and MetastasisCell, 2012
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Coordinated regulation of myeloid cells by tumoursNature Reviews Immunology, 2012
- Immunologic Correlates of the Abscopal Effect in a Patient with MelanomaThe New England Journal of Medicine, 2012
- The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive ImmunityCancer Cell, 2010
- Immunity, Inflammation, and CancerCell, 2010
- PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- PD-L1 regulates the development, maintenance, and function of induced regulatory T cellsThe Journal of Experimental Medicine, 2009
- Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapyNature Medicine, 2007