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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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

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Figure 2

IR and PD-L1 blockade synergistically amplify the antitumor effect.

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IR and PD-L1 blockade synergistically amplify the antitumor effect. (A) ...
(A) Combination of anti–PD-L1 (αPD-L1) and IR significantly enhanced the inhibition of TUBO tumor growth. BALB/c mice were inoculated s.c. on day 0 with 1 × 106 TUBO cells. Tumors locally received one 12-Gy dose on day 14 and/or 200 μg anti–PD-L1 (clone 10F.9G2) or isotype control i.p. every three days for a total of four times. **P < 0.01; ***P < 0.001. (B) Combination therapy greatly delayed MC38 tumor growth compared with single treatments. C57BL/6 mice were injected s.c. on day 0 with 1 × 106 MC38 cells. Tumors received 20 Gy on day 8, and antibodies were started on day 8 and administered as described in A. *P < 0.05; ***P < 0.001. (C) Tumor-free mice that underwent combination therapy were resistant to the tumor rechallenge. Thirty days after tumor eradication, the mice treated as in A were rechallenged with 2 × 106 TUBO cells on the opposite flank. (D) Systemic effect of combination treatment greatly reduced the growth of secondary tumors. TUBO tumors on the right flank were treated with 12 Gy or anti–PD-L1 alone, or with 12 Gy plus anti–PD-L1, as described in A. Tumors on the left flank were measured and monitored. Representative data are shown from three (A) or two (B–D) experiments conducted with 6 to 8 (A and D), 5 (B), or 4 (C) mice per group.