Programmed cell death receptor 1 (PD-1) and its ligand, PD-L1, are important immune checkpoint proteins. Although antibodies that block PD-1/PD-L1 have shown promising clinical efficacy in a subset of cancer patients, the detailed cellular and molecular mechanisms behind anti-PD-1 and anti-PD-L1 immunotherapy are not well defined. Specifically, the way in which PD-L1 contributes to immune suppression on tumor and non-tumor cells remains controversial. By selectively blocking PD-L1 on either tumor or non-tumor cells, we demonstrated that PD-L1 from both sources suppressed the anti-tumor T-cell response. Blocking PD-L1 on either tumor cells or non-tumor cells inhibited tumor growth and enhanced immune cell infiltration, as well as the tumor-specific T-cell response. Further, simultaneously blocking tumor- and non-tumor-derived PD-L1 maximized anti-tumor T-cell responses and demonstrated synergy. In addition, the relative contribution of PD-L1 on tumor and non-tumor cells to immune suppression depended on the PD-L1 expression level. Lastly, we found that the F4/80 receptor was involved in the anti-tumor effect of PD-L1 blockade. Taken together, our data indicate that PD-L1 on both tumor and non-tumor cells is critical for T-cell inhibition, which provides new directions for the optimization of PD-L1-blocking antibodies and the development of clinical biomarker strategies.
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We thank Dr. Hans Schreiber for providing the B16-OVA cells and Dr. Michelle Xu and Dr. Jie Zhao for their useful comments on this paper. X.W was supported by Special development fund of Shanghai Zhangjiang National Innovation Demonstration Zone (201609-JA-ZBC1085-009). X.Y. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (TP2015013), Shanghai Pujiang Program (15PJ1404500), National Natural Science Foundation of China (81671643) and the Recruitment Program of Global Experts (People’s Republic of China).
The authors declare no competing interests.
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