Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
Liufu Deng, … , Ralph R. Weichselbaum, Yang-Xin Fu
Liufu Deng, … , Ralph R. Weichselbaum, Yang-Xin Fu
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):687-695. https://doi.org/10.1172/JCI67313.
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Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

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.

Authors

Liufu Deng, Hua Liang, Byron Burnette, Michael Beckett, Thomas Darga, Ralph R. Weichselbaum, Yang-Xin Fu

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Figure 5

CD8+ T cells mediate the reduction of MDSCs in IR and anti–PD-L1 combination treatment.

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CD8+ T cells mediate the reduction of MDSCs in IR and anti–PD-L1 combina...
TUBO tumor–bearing mice were treated with IR and antibodies as described in Figure 2A and Figure 3A. Ten days after IR, the tumors were removed. (A) Immunofluorescence staining of frozen tumor sections. Top row, untreated tumor; Bottom row, tumor treated with IR and anti–PD-L1. Scale bars: 100 μm; original magnification, ×4. Inset scale bars: 5 μm; original magnification, ×100. (B) Quantification of distance from CD11b+Gr1+ cells to the closest CD8+ T cell in a high-power field (×40). Fifteen to eighteen high-power fields were counted for each section. **P < 0.01. Sections were obtained from three tumors per group. The quantification performed on the individual tumor from each group is shown in each histogram. (C) Representative dot plots of MDSCs gated on a CD45+ cell population. (D) The reduction of the proportion of MDSCs with combination therapy was rescued after the depletion of CD8+ T cells. **P < 0.01. Representative data are shown from two (A–D) experiments conducted with 3 (A and B) or 4 (C and D) mice per group.