Circulating levels of PD-L1 and Galectin-9 are associated with patient survival in surgically treated Hepatocellular Carcinoma independent of their intra-tumoral expression levels

Sideras, Kostandinos; Man, Robert A. de; Harrington, Susan M.; Polak, Wojciech; Zhou, Guoying; Schutz, Hannah M.; Pedroza-González, Alexander; Biermann, Katharina; Mancham, Shanta; Hansen, Bettina E.; Takkenberg, R. Bart; Pan, Qiuwei; IJzermans, Jan N.M.; Sleijfer, Stefan; Sprengers, Dave; Dong, Haidong; Kwekkeboom, Jaap; Bruno, Marco J.

doi:10.1038/s41598-019-47235-z

Cited by 43 publications

(28 citation statements)

References 53 publications

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“…Second, high sPD-L1 is a positive prognostic indicator in a minority of tumor types, including stomach adenocarcinoma. 38,39 Stomach adenocarcinoma is one of the only two malignancies for which our analysis found an association between lower PD-L1 protein-to-mRNA ratios and improved outcomes. Different sPD-L1 cleavage products generated by ADAM10 and/or ADAM17 either alone or in sequence may have different effects on the PD-1 receptor, and different resistance mechanisms may further account for these differences.…”

Section: Discussionmentioning

confidence: 75%

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

et al. 2020

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2020) ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance, ABSTRACT ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10-and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy. ARTICLE HISTORY Materials and methods Cell cultureMalignant cell lines 786-0, Karpas-299, and Du145 (ATCC) were grown in RPMI 1640 (Invitrogen) supplemented by 10%

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Section: Discussionmentioning

confidence: 75%

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

et al. 2020

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“…Although SB cell-derived EVs expressed PD-L1 (Supplemental Figure 2, D and E), incubating BMDMs with SB EVs did not alter macrophage-associated PD-L1 (Supplemental Figure 2F). PD-L1 may also be present in a circulating or soluble form with immunosuppressive properties that facilitate cancer progression (28,29). Indeed, we identified soluble PD-L1 in conditioned medium from SB cells (Figure 2I), implying that Taken together, these results suggest that, although cancer cells transfer a small amount of PD-L1 to TAMs, this transferred soluble PD-L1 is not immunosuppressive based on its impact on T cells.…”

Section: Resultsmentioning

confidence: 85%

Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma

Loeuillard¹,

Yang²,

Buckarma³

et al. 2020

Journal of Clinical Investigation

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234

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Figure 1. TAMs are the predominant source of PD-L1 in CCA. (A) Representative images (left and middle panels) of PD-L1 (brown staining, black arrowhead) plus CD68 (red staining, red arrowhead) coimmunostaining (n = 33) and PD-L1 (brown staining) plus CK-19 (red staining) coimmunostaining (n = 18) in human resected CCA specimens. Percentage of patients with positive PD-L1/CD68 costaining and PD-L1/CK19 costaining, respectively (right panel). Scale bars: 40 μm. (B) Histograms show expression of PD-L1 + macrophages in human CCA tumors. (C-F) Flow cytometry analysis of normal WT mouse livers (from WT mice without tumors) as well as adjacent livers and tumors of mice 28 days after orthotopic implantation of 1 × 10 6 SB (murine CCA) cells. (C) Percentage of PD-L1 + macrophages (Mφ) of total macrophages (CD45 + CD11b + F4/80 + ) in WT mouse normal liver, tumor-adjacent liver, or tumor. Fluorescence Minus One (FMO) controls were used for each independent experiment to establish gates (See Supplemental Figure 1A for gating strategy) (n ≥ 8). Representative histograms show expression of PD-L1 + macrophages. (D) Percentage of CD206 + TAMs (left panel) and PD-L1 + CD206 + TAMs (middle panel) of F4/80 int macrophages (CD45 + CD11b + F4/80 int ) in WT mouse liver, tumor-adjacent liver, or tumor. Representative contour plots (right panel) show CD206 and PD-L1 expression of F4/80 int macrophages (n ≥ 7). (E) Percentage of PD-L1 + CD206macrophages or PD-L1 + CD206 + macrophages (CD11b + F4/80 + ) of CD45 + cells from SB tumors (n = 28). (F) Percentage of PD-L1 expression in myeloid cells from SB tumors.

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“…Another binding partner for TIM-3 is the conserved s-type lectin galectin-9 (Gal-9), which is a pleiotropic immune modulator. Besides TIM-3, Gal-9 has numerous binding partners and can be secreted by cancer cells via various mechanisms [177]. It has been recently recognized that Gal-9 inhibits the production of IFNα by mouse and human pDCs stimulated with various TLR7/9 ligands.…”

Section: Tumor-derived Factorsmentioning

confidence: 99%

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

Bencze

Fekete

Pázmándi

2021

IJMS

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One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.

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Circulating levels of PD-L1 and Galectin-9 are associated with patient survival in surgically treated Hepatocellular Carcinoma independent of their intra-tumoral expression levels

Cited by 43 publications

References 53 publications

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

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