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

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

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

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Figure 4

Expression and role of APC PD-L1 in immunosuppression.

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Expression and role of APC PD-L1 in immunosuppression. (A and B) PD-L1 e...
(A and B) PD-L1 expression in immune cells in MC38 tumors and ID8 ascites (A) and TDLNs (B). PD-L1 expression was analyzed by flow cytometry analysis in immune cell subsets in tumor tissues. Data are expressed as mean ± SEM. n = 3. (C–F) Effect of anti–PD-L1 on T cell effector cytokine expression. WT, PD-1–/–, and PD-L1–/– splenocytes were activated with anti-CD3, anti-CD28, and anti–PD-L1 or isotype control. T cell IFN-γ (C and D) and TNF-α (E) production were measured by flow cytometry. Results are expressed as mean ± SEM (n = 3). t test was used for 2-way comparisons. *P < 0.05. (F) Effect of anti–PD-L1 on T cell effector cytokine expression. WT and PD-1–/– T cells were activated in the presence of WT or PD-L1–/– DCs. T cell IFN-γ and TNF-α production in T cells in the presence of anti–PD-L1 or isotype control. Representative replicates are shown. n = 3. t test was used for 2-way comparisons. *P < 0.05. (G and H) PD-L1–/– mice were adoptively transferred with WT or PD-L1–/– DCs or macrophages. Mice were given MC38 tumor cells and treated with anti–PD-L1 or isotype control (rIgG1). n = 3–7. Tumor volume was monitored. Wilcoxon test was used for 2-way comparisons. *P < 0.05; **P < 0.01. (I and J) ID8 tumor–associated peritoneal WT and PD-L1–/– APCs were transferred into ID8 tumor–bearing PD-L1–/– mice. These mice were treated with anti–PD-L1 and isotype IgG1. (I) Tumor progression was monitored by Xenogen IVIS Spectrum. (J) T cell effector cytokines were analyzed with intracellular staining in ID8 tumor ascites. t test was used for 2-way comparisons. n = 7. *P < 0.05. (K and L) Effect of anti–PD-L1 on human T cell cytokine expression. Human T cells were activated with anti-CD3 and anti-CD28 and DCs, macrophages, or fixed tumor cells. T cell IL-2 production was analyzed by flow cytometry analysis. Data are expressed as representative flow cytometry analysis data (K) and individual dot points for each sample (L). n = 5. Wilcoxon test was used for 2-way comparisons. *P < 0.05.