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

Tang, Haidong; Liang, Yong; Anders, Robert A.; Taube, Janis M.; Qiu, Xiangyan; Mulgaonkar, Aditi; Liu, Xin; Harrington, Susan M.; Guo, Jingya; Xin, Yangchun; Xiong, Yahong; Nham, Kien; Silvers, William; Hao, Guiyang; Sun, Xiankai; Chen, Mingyi; Hannan, Raquibul; Qiao, Jian; Dong, Haidong; Peng, Hua; Fu, Yang Xin

doi:10.1172/jci96061

Cited by 408 publications

(398 citation statements)

References 37 publications

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“…6,39,40 We made a similar observation when incubating total splenocytes isolated from wild-type (WT), but not PD-L1 knockout (KO) mice with anti-PD-L1 antibody (Figure 3a; compare lanes 1–2 and 3–4 in Figure 3b), thus demonstrating antibody specificity. However, co-culture of WT splenocytes with WT adipocytes significantly dampened the anti-PD-L1 antibody effect on CD8 + IFNγ + T cells (compare lanes 1–2 and 5–6 in Figure 3b).…”

Section: Resultsmentioning

confidence: 56%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Section: Resultsmentioning

confidence: 56%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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“…Very recently, PD‐L1 in tumor cells has been shown to be dispensable for the responses to PD‐L1 blockade therapy after tumor establishment in three different models (MC38, A20, and E.G7). Moreover, PD‐L1 appeared not only to be highly expressed in myeloid cells, but also to contribute to the inhibition of T cell activation, since blocking PD‐L1 signaling by Ab releases such inhibition, leading to better T cell activation (Tang et al., ). Recently, we analyzed the mechanisms involved in the interplay between MDSCs and activated T cells.…”

Section: Commentarymentioning

confidence: 99%

Methods to Measure MDSC Immune Suppressive Activity In Vitro and In Vivo

et al. 2018

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This unit presents methods to assess the immunosuppressive properties of immunoregulatory cells of myeloid origin, such as myeloid‐derived suppressor cells (MDSCs), both in vitro and in vivo in mice, as well as in biological samples from cancer patients. These methods could be adapted to test the impact of different suppressive populations on T cell activation, proliferation, and cytotoxic activity; moreover, they could be useful to assess the influence exerted by genetic modifications, chemical inhibitors, and drugs on immune suppressive pathways © 2018 by John Wiley & Sons, Inc.

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“…As a ligand of PD‐1, PD‐L1 is expressed on many types of cancer cells with therapeutic values . Together with another ligand PD‐L2, PD‐L1 is also expressed on antigen presenting cells (APCs, Figure ) to negatively regulate T‐cell immune function and induce T‐cell exhaustion . As tumour cells use PD‐L1 to inhibit T‐cell immune function resulting in tumour cell evasion from immune surveillance, inhibition of PD‐L1 restores T‐cell function and destroys cancer cells .…”

Section: The T‐cell Negative Regulatory Checkpointsmentioning

confidence: 99%

“…As tumour cells use PD‐L1 to inhibit T‐cell immune function resulting in tumour cell evasion from immune surveillance, inhibition of PD‐L1 restores T‐cell function and destroys cancer cells . However, PD‐L1 presentation by APC may play a more dominant role than that of PD‐L1 on the tumour cell surface in murine tumour models …”

Section: The T‐cell Negative Regulatory Checkpointsmentioning

confidence: 99%

“…32 Together with another ligand PD-L2, PD-L1 is also expressed on antigen presenting cells (APCs, Figure 1) to negatively regulate T-cell immune function and induce T-cell exhaustion. 33 As tumour cells use PD-L1 to inhibit Tcell immune function resulting in tumour cell evasion from immune surveillance, 32,34 inhibition of PD-L1 restores T-cell function and destroys cancer cells. 32,35 However, PD-L1 presentation by APC may play a more dominant role than that of PD-L1 on the tumour cell surface in murine tumour models.…”

Section: The T-cell Neg Ative Reg Ul Atory Checkp Ointsmentioning

confidence: 99%

See 1 more Smart Citation

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

Wang

et al. 2019

Clin Exp Pharma Physio

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Summary Recent clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein‐1/PD‐1 ligand 1 (PD‐1/PD‐L1) has initiated a new era in the treatment of metastatic cancer. However, greater challenges remain to treat all cancers. The molecular architecture in the immune synapse constituting positive engagements for immune activation and negative checkpoints against immune hyperactivity is regulated dynamically by interaction between proteostasis and tumour microenvironment. This article reviews recent progresses in our understandings of the cellular and molecular mechanisms of the negative checkpoint PD‐1/PD‐L1 behaviours in immune tolerance of tumourigenesis and metastasis. We provide an overview on PD‐L1 gene expression regulation, protein turnover, intra‐ and extracellular trafficking, exosome‐mediated inter‐cellular transport, molecular interface peptide mimetics, inhibitory chemical compounds such as metformin, and antibody dynamics. We summarise PD‐L1 post‐translational modifications including glycosylation, palmitoylation, phosphorylation and ubiquitination, reflecting future research directions and opportunities in identifying tumour‐specific signalling targets, their regulatory molecules and pathways for intervention into various types of cancers.

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

Cited by 408 publications

References 37 publications

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Methods to Measure MDSC Immune Suppressive Activity In Vitro and In Vivo

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

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