Programmed death–ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1–negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti–PD-L1–mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti–PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.
Haidong Tang, Yong Liang, Robert A. Anders, Janis M. Taube, Xiangyan Qiu, Aditi Mulgaonkar, Xin Liu, Susan M. Harrington, Jingya Guo, Yangchun Xin, Yahong Xiong, Kien Nham, William Silvers, Guiyang Hao, Xiankai Sun, Mingyi Chen, Raquibul Hannan, Jian Qiao, Haidong Dong, Hua Peng, Yang-Xin Fu