PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression

Jan 17, 2018The Journal of clinical investigation

PD-L1 on normal cells is needed for tumor shrinkage caused by PD-L1 blockade

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Abstract

Anti-PD-L1 antibodies accumulate in tumor tissues regardless of PD-L1 expression on tumor cells.

PD-L1 expression on tumor cells is not essential for the effectiveness of anti-PD-L1 therapy.
PD-L1 in host myeloid cells is critical for an effective response to checkpoint blockade.
PD-L1 signaling in specific antigen-presenting cells negatively affects T cell activation.
Limiting T cell movement reduces the effectiveness of PD-L1 blockade within tumors.
Findings suggest that PD-L1 in antigen-presenting cells is more important than PD-L1 on tumor cells for therapy response.

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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.

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PD-L1 on host cells is essential for PD-L1 blockade–mediated tumor regression

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