title: 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.forename: Liufu
authors.initials: L
authors.lastname: Deng
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.forename: Byron
authors.initials: B
authors.lastname: Burnette
authors.forename: Michael
authors.initials: M
authors.lastname: Beckett
authors.forename: Thomas
authors.initials: T
authors.lastname: Darga
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D022423:Myeloid Cells / Q000166:cytology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000532:radiotherapy; D011839:Radiation, Ionizing; D013997:Time Factors; D059016:Tumor Microenvironment
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse