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 February 3, 2014; First published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):687-695. https://doi.org/10.1172/JCI67313.
View: Text | PDF
Categories: Research Article Oncology

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

×

Figure 1

The profile of PD-L1 and PD-1 expression in tumor microenvironments is altered after IR.

Options: View larger image (or click on image) Download as PowerPoint
The profile of PD-L1 and PD-1 expression in tumor microenvironments is a...
BALB/c mice were injected s.c. into the flank with 1 × 106 TUBO cells. On day 14, mice were locally treated with one 12-Gy dose of IR. Three days after IR, tumors were removed and digested into single-cell suspensions, which were blocked with anti-FcR mAbs and then subjected to surface staining. PD-L1 expression on myeloid cells and tumor cells (A) and PD-1 expression on T cells (B). Representative data are shown from three (A and B) experiments conducted using 3 mice per group.