Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α

Hartley, Genevieve; Regan, Daniel P.; Guth, Amanda; Dow, Steven

doi:10.1007/s00262-017-1955-5

Cited by 82 publications

(70 citation statements)

References 43 publications

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“…It remains unknown whether other costimulatory pathways are affected. Our coexpression data in tumor-infiltrating myeloid cells further support the biological significance of the interaction and are in line with previous findings of PD-L1 expression on tumorinfiltrating macrophages (34).…”

Section: Discussionsupporting

confidence: 80%

PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface

Chaudhri

Xiao

Klee

et al. 2018

Cancer Immunology Research

149

124

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Programmed death ligand 1 (PD-L1)-mediated immunosuppression regulates peripheral tolerance and is often co-opted by tumors to evade immune attack. PD-L1 binds to PD-1 but also binds to B7-1 (CD80) to regulate T-cell function. The binding interaction of PD-L1 with B7-1 and its functional role need further investigation to understand differences between PD-1 and PD-L1 tumor immunotherapy. We examined the molecular orientation of PD-L1 binding to B7-1 using cell-to-cell binding assays, ELISA, and flow cytometry. As expected, PD-L1-transfected cells bound to PD-1-transfected cells, and B7-1 cells bound to CD28 or CTLA-4-transfected cells; however, PD-L1 cells did not bind to B7-1 cells. By ELISA and flow cytometry with purified proteins, we found PD-L1 and B7-1 had a strong binding interaction only when PD-L1 was flexible. Soluble PD-1 and B7-1 competed for binding to PD-L1. Binding of native PD-L1 and B7-1 in cis on the same cell surface was demonstrated with NanoBiT proximity assays. Thus, PD-L1-B7-1 interaction can occur in cis on the same cell but not in trans between two cells, which suggests a model in which PD-L1 can bend via its 11-amino acid, flexible stalk to bind to B7-1 in cis, in a manner that can competitively block the binding of PD-L1 to PD-1 or of B7-1 to CD28. This binding orientation emphasizes the functional importance of coexpression of PD-L1 and B7-1 on the same cell. We found such coexpression on tumor-infiltrating myeloid cells. Our findings may help better utilize these pathways in cancer immunotherapy.

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Section: Discussionsupporting

confidence: 80%

PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface

Chaudhri

Xiao

Klee

et al. 2018

Cancer Immunology Research

149

124

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“…These activated PD‐L1 + monocytes suppressed tumour‐specific T cell proliferation, cytokine production, and cytotoxic potential in vitro and also fostered tumour growth in NOD/SCID mice bearing human tumours . Corresponding to TAM study showed that the tumour‐conditioned media strongly induced PD‐L1 expression on bone marrow‐derived monocytes mediated by TNF‐α . Besides that, a recent study showed that CD14 + CD68 hi CD163 hi intratumoural monocyte/M2 macrophages had pronounced dual protein expression of PD‐L1/PD‐L2 in both classical Hodgkin lymphoma (cHL) and diffuses large B‐cell lymphoma (DLBCL) .…”

Section: Discussionmentioning

confidence: 89%

“…10 Corresponding to TAM study showed that the tumourconditioned media strongly induced PD-L1 expression on bone marrow-derived monocytes mediated by TNF-α. 21 Besides that, a recent study showed that CD14 + CD68 hi CD163 hi intratumoural monocyte/ M2 macrophages had pronounced dual protein expression of PD-L1/ PD-L2 in both classical Hodgkin lymphoma (cHL) and diffuses large B-cell lymphoma (DLBCL). 22 Furthermore, other investigators have reported the increase in PD-L1-expressing CD68 + macrophage in circulating blood of ovarian cancer patients, and the expression of PD-L1 on TAM promoted apoptosis of T cells via interaction with PD-1 on CD8 + T cells.…”

Section: Corelation Of M2 Macrophages and Pd-l1mentioning

confidence: 99%

Autocrine VEGF signalling on M2 macrophages regulates PD‐L1 expression for immunomodulation of T cells

Lai

Wahyuningtyas

Aui

et al. 2018

J Cellular Molecular Medi

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M2‐polarized macrophages, on one hand, can promote tumour vascularization by producing proangiogenic factors, such as vascular endothelial growth factor (VEGF). On the other hand, the expression of VEGF receptors (VEGFR) in this cell lineage was also reported. Although the function of VEGF/VEGFR axis plays a pivotal role in macrophages infiltration and angiogenesis, however, there is still lack of the direct evidence to show the role of VEGF as an autocrine operating in M2 macrophages, particularly for immunomodulation. In our study, we surprisingly discovered that M2 macrophages polarized by baicalin can simultaneously express VEGF and its receptors. Taking advantage of this unique culture system, we were able to investigate the biological activity of M2 macrophages in response to the autocrine VEGF milieu. Our results showed that the expression of programmed death‐ligand 1 (PD‐L1) on M2 macrophages was significantly up‐regulated in autocrine VEGF milieu. Through the blockade of autocrine VEGF signalling, PD‐L1 expression on M2 macrophages was dramatically down‐regulated. Furthermore, transplantation of PD‐L1+ M2 macrophage stimulated by autocrine VEGF into allogeneic mice significantly suppressed host CD4+/CD8+ T cells in the peripheral blood and increased CD4+ CD25+ regulatory T cells in the bone marrow. In conclusion, our findings provide a novel biological basis to support the current successful strategy using combined VEGF/PD‐1 signalling blockade in cancer therapy.

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“…The goal of the present study was to investigate the role that PD-L1 expression plays in regulating biological functions of macrophages, particularly TAMs. TAMs express PD-L1, and we reported that TAM PD-L1 expression was regulated by locally produced TNFa (18). In a screen of several different tumors in humans, PD-L1-expressing macrophages were more abundant than PD-L1-expressing tumor cells (15).…”

Section: Introductionmentioning

confidence: 91%

“…Tibias and femurs were collected from healthy mice and bone marrow cells were harvested as described previously (18). Tissues from PD-L1 À/À C57Bl/6 mice were a kind gift from Raphael Nemenoff and Howard Li (University of Colorado Denver, Aurora, CO).…”

Section: Monocyte Isolation and Macrophage Culturementioning

confidence: 99%

Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation

Hartley

Chow

Ammons

et al. 2018

Cancer Immunology Research

271

234

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Tumor-associated macrophages (TAMs) express programmed cell death ligand 1 (PD-L1) and contribute to the immune-suppressive tumor microenvironment. Although the role of the PD-L1 and PD-1 interaction to regulate T-cell suppression is established, less is known about PD-L1 signaling in macrophages and how these signals may affect the function of TAMs. We used and models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on TAM responses. Treatment of mouse and human macrophages with PD-L1 antibodies increased spontaneous macrophage proliferation, survival, and activation (costimulatory molecule expression, cytokine production). Similar changes were observed in macrophages incubated with soluble CD80 and soluble PD-1, and in PD-L1 macrophages. Macrophage treatment with PD-L1 antibodies upregulated mTOR pathway activity, and RNAseq analysis revealed upregulation of multiple macrophage inflammatory pathways. treatment with PD-L1 antibody resulted in increased tumor infiltration with activated macrophages. In tumor-bearing RAG mice, upregulated costimulatory molecule expression by TAMs and reduced tumor growth were observed. Combined PD-1/ PD-L1 antibody treatment of animals with established B16 melanomas cured half of the treated mice, whereas treatment with single antibodies had little therapeutic effect. These findings indicate that PD-L1 delivers a constitutive negative signal to macrophages, resulting in an immune-suppressive cell phenotype. Treatment with PD-L1 antibodies reverses this phenotype and triggers macrophage-mediated antitumor activity, suggesting a distinct effect of PD-L1, but not PD-1, antibody treatment. .

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Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α

Cited by 82 publications

References 43 publications

PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface

PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface

Autocrine VEGF signalling on M2 macrophages regulates PD‐L1 expression for immunomodulation of T cells

Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation

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