Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade–mediated tumor regression

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Abstract

Programmed death-1 ligand (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1– and PD-1–deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti–PD-1 alone or in combination with anti–CTLA-4. Thus, PD-L1–expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.

Authors

Heng Lin, Shuang Wei, Elaine M. Hurt, Michael D. Green, Lili Zhao, Linda Vatan, Wojciech Szeliga, Ronald Herbst, Paul W. Harms, Leslie A. Fecher, Pankaj Vats, Arul M. Chinnaiyan, Christopher D. Lao, Theodore S. Lawrence, Max Wicha, Junzo Hamanishi, Masaki Mandai, Ilona Kryczek, Weiping Zou