Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn’s disease

Robertson, Jack; Haas, Carolin; Pele, Laetitia; Monie, Tom P.; Charalambos, Charles; Parkes, Miles; Hewitt, Rachel E.; Powell, Jonathan J.

doi:10.1038/srep26747

Cited by 31 publications

(27 citation statements)

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“…This may underlie the PD‐L1 overexpression in these diseases, as we observed. Indeed, PD‐L1 epithelial expression has been described in a small number of IBD, 20 UC 21 and CD cases 22 . Additionally, and in line with our findings, increased PD‐L1 epithelial expression has also been described in pancreatic ductal cells of patients with type 2 autoimmune pancreatitis, a condition that is often associated with UC, and thus probably pathogenetically related 23…”

Section: Discussionsupporting

confidence: 89%

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

et al. 2020

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Aims Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune‐mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non‐tumoral cells of tissues affected by immune‐related adverse effects has been described in ICI‐associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death‐1 (PD‐1) and its ligand, programmed death‐ligand 1 (PD‐L1), in PD‐1 inhibitor‐associated colitis (PD1i colitis). Methods and results PD‐1 and PD‐L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics—infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD‐L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD‐1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD‐1 inhibitors. Conclusions Although our results do not justify the use of PD‐L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD‐L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory‐mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune‐related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.

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Section: Discussionsupporting

confidence: 89%

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

et al. 2020

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“…However, those studies where performed mostly by flow cytometry, where selective enrichment and gating of the professional immune cells did not include CMF analysis. Furthermore, a deficiency in professional antigen-presenting cells PD-L1 induction was reported in small intestinal lymphoid patches in CD ( 25 , 26 ). We confirmed that PD-L1 was moderately increased in the UC and CD epithelial cells as has been previously seen by Nakazawa et al ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…The intricate role of PD-L1 and PD-L2 in the dysregulation of Th cell responses in human IBD remains unclear and the sparse reports are contradictory. PD-L1 is upregulated in the intestinal epithelium, macrophages, and B cells in both forms of IBD ( 21 , 24 ), yet expression of inducible PD-L1 appears to be impaired in CD-derived monocytes and ileal APCs ( 25 , 26 ). Finally, recent reports indicate that while mAbs against PD-1 and anti-PD-L1 are currently successfully used in clinics for treatment of several solid tumors, one of the main immune-related adverse effect (irAE) of the immune checkpoint blockade therapy is development of chronic diarrhea and enterocolitis ( 27 – 29 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn’s Disease and Determines Their Capacity to Suppress Th1 Cells

Beswick¹,

Grim

Singh

et al. 2018

Front. Immunol.

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Background and AimsThe role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses.MethodsTissues and cells derived from Crohn’s disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture.ResultsA significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses.ConclusionWe present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.

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“…While the AMCP is inert, its cargo (notably peptidoglycan) appears to actively promote tolerance in the normal gut by up-regulating the co-regulatory molecule, PD-L1, on APCs that are recipients of endogenous cargo-bearing AMCP 17, 33. However, this is not the case in Crohn's disease 41 . We have recently shown that APCs of the AMCP pathway display a selective failure in expression of PD-L1 in this disorder 41 and hence hypothesized that this may lead to a loss of tolerance towards luminal contents—a hallmark of the disease 42 .…”

Section: Discussionmentioning

confidence: 99%

Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery

Pele

Haas

Hewitt

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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Amorphous magnesium-substituted calcium phosphate (AMCP) nanoparticles (75-150 nm) form constitutively in large numbers in the mammalian gut. Collective evidence indicates that they trap and deliver luminal macromolecules to mucosal antigen presenting cells (APCs) and facilitate gut immune homeostasis. Here, we report on a synthetic mimetic of the endogenous AMCP and show that it has marked capacity to trap macromolecules during formation. Macromolecular capture into AMCP involved incorporation as shown by STEM tomography of the synthetic AMCP particle with 5 nm ultra-fine iron (III) oxohydroxide. In vitro, organic cargo-loaded synthetic AMCP was taken up by APCs and tracked to lysosomal compartments. The AMCP itself did not regulate any gene, or modify any gene regulation by its cargo, based upon whole genome transcriptomic analyses. We conclude that synthetic AMCP can efficiently trap macromolecules and deliver them to APCs in a silent fashion, and may thus represent a new platform for antigen delivery.

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Intestinal APCs of the endogenous nanomineral pathway fail to express PD-L1 in Crohn’s disease

Cited by 31 publications

References 31 publications

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

Expression of Programmed Death-Ligand 1 by Human Colonic CD90+ Stromal Cells Differs Between Ulcerative Colitis and Crohn’s Disease and Determines Their Capacity to Suppress Th1 Cells

Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery

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