Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice

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

Research output: Contribution to journalArticle

845 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)687-695
Number of pages9
JournalJournal of Clinical Investigation
Volume124
Issue number2
DOIs
StatePublished - Feb 3 2014

ASJC Scopus subject areas

  • Medicine(all)

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