CoChat
Sign Up
Cited by 49

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Analysis of expression of the PD-1/PD-L1 immune checkpoint system and its prognostic impact in gastroenteropancreatic neuroendocrine tumors

Sampedro-Núñez, Miguel, Serrano-Somavilla, Ana, Adrados, Magdalena, Cameselle-Teijeiro, José M., Blanco-Carrera, Concepción, Cabezas-Agricola, José Manuel, Martínez-Hernández, Rebeca, Martín-Pérez, Elena, Muñoz de Nova, José Luis, Díaz, José Ángel, García-Centeno, Rogelio, Caneiro-Gómez, Javier, Abdulkader, Ihab, González-Amaro, Roberto, Marazuela, Mónica·2018·Scientific Reports
DOI 10.1038/s41598-018-36129-1PMC PMC6292913
Open this paper in CoChat — free account

Abstract

The immune checkpoint based therapy targeting the programmed death-1 (PD-1) receptor and its PD-L1 ligand has recently been approved for the therapy of different malignant conditions, but not yet for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this context, we evaluated the expression of PD-1 and PD-L1 in GEP-NETs and its potential correlations with clinical outcomes. Expression of PD-1/PD-L1 was analyzed by immunohistochemistry in 116 GEP-NETs and 48 samples of peritumoral tissue. In addition, the expression of these molecules was assessed by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with GEP-NETs (n = 32) and healthy controls (n = 32) and in intratumoral mononuclear cells (TMCs) (n = 3). Expression of PD-L1 and PD-1 was detected by immunohistochemistry in 6% and 1% of tumor tissue samples, respectively, and in 8% of peritumoral tissue samples, for both markers. We also observed that PD-1 expression by TMCs was associated with metastatic disease at diagnosis, and the levels of circulating PD-1+ PBMCs were associated with progressive disease upon follow-ups. In addition, circulating PD-1+ PBMCs were significantly correlated with PD-L1 expression by tumor cells. Our data suggest that PD-1/PD-L1 is expressed in 1 to 8% of GEP-NETs, and that this feature is significantly associated with disease evolution (p < 0.01).

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-018-36129-1

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Representative immunohistochemical staining patterns of PD-L1 in GEP-NETs. (a–d) TMA sections of a G3 pancreatic NET. (a) Positive membranous staining for PD-L1 in cancer cells. (b) CD163 expression in peritumoral macrophages. (c) CD3 expression in peritumoral lymphocytes. (d) Negative expression of PD-1. (e–h) TMA sections of a G2 intestinal NET. (e) Positive membranous staining for PD-L1 in peritumoral infiltrating cells. (f) CD163 expression in peritumoral macrophages. (g) CD3 expression in peritumoral lymphocytes. (h) Positive expression of PD-1. Original magnification with 20x and 40x (insets). Scale bar for 100 µm is represented with a line for each panel. (i) PD-L1 expression was measured by IHC in a set of TMAs (n = 164) of GEP-NETs. Bar graph values represent the percentage of samples with positivity for PD-L1 expression in the peritumoral and in tumoral tissue. (j–o) Immunofluorescence (IF) staining in a G3 intestinal NET. (j,m) Simple IF with PD-L1 (red). (k) Simple IF with CD68 (green). (l) Double IF with CD68 (green) and PD-L1 (red). (n) Simple IF with CD3 (green). (o) Double IF with CD3 (green) and PD-L1 (red). Scale bar for 25 µm is represented with a line for each panel.
Figure 1 Representative immunohistochemical staining patterns of PD-L1 in GEP-NETs. (a–d) TMA sections of a G3 pancreatic NET. (a) Positive membranous staining for PD-L1 in cancer cells. (b) CD163 expression in peritumoral macrophages. (c) CD3 expression in peritumoral lymphocytes. (d) Negative expression of PD-1. (e–h) TMA sections of a G2 intestinal NET. (e) Positive membranous staining for PD-L1 in peritumoral infiltrating cells. (f) CD163 expression in peritumoral macrophages. (g) CD3 expression in peritumoral lymphocytes. (h) Positive expression of PD-1. Original magnification with 20x and 40x (insets). Scale bar for 100 µm is represented with a line for each panel. (i) PD-L1 expression was measured by IHC in a set of TMAs (n = 164) of GEP-NETs. Bar graph values represent the percentage of samples with positivity for PD-L1 expression in the peritumoral and in tumoral tissue. (j–o) Immunofluorescence (IF) staining in a G3 intestinal NET. (j,m) Simple IF with PD-L1 (red). (k) Simple IF with CD68 (green). (l) Double IF with CD68 (green) and PD-L1 (red). (n) Simple IF with CD3 (green). (o) Double IF with CD3 (green) and PD-L1 (red). Scale bar for 25 µm is represented with a line for each panel.CC BY · PubMed Central
Figure 2 Characterization of the immune cell infiltrate in GEP-NETs. (a–d) Serial sections of a pancreatic neuroendocrine tumor. (a) Intense staining for CD3 in TILs of NET tissue. (b) Staining for FOXP3 in some TILs. (c) Staining for PD-1 in some TILs, (d) hematoxylin-eosin staining. Original magnification with 20x and 40x (insets). Scale bar for 100 µm is represented with a line for each panel. (e) CD3, (f) FOXP3 and (g) PD-1 were measured by IHC in a set of TMAs (n = 164) of GEP-NETs, including primary and metastatic tissue. Values represent boxplot of CD3 IHC score and bar graphs of the percentage of samples with positivity for FOXP3 and PD-1 expression in the tumor tissue and in the peritumoral normal tissue. Asterisks indicate significant differences between tumor and peritumoral tissues (p-values for Fisher’s Exact Test: *p < 0.05). (h–k) Immunofluorescence showing different markers in TILs: h) Double immunofluorescence with CD3 (green) and PD-1 (blue). (i) Double immunofluorescence with CD3 (green) and FOXP3 (red). (j) Double immunofluorescence with PD-1 (blue) and FOXP3 (red). (k) Triple immunofluorescence with CD3 (green), PD-1 (blue) and FOXP3 (red). Scale bar for 100 µm is represented with a line for each panel.
Figure 2 Characterization of the immune cell infiltrate in GEP-NETs. (a–d) Serial sections of a pancreatic neuroendocrine tumor. (a) Intense staining for CD3 in TILs of NET tissue. (b) Staining for FOXP3 in some TILs. (c) Staining for PD-1 in some TILs, (d) hematoxylin-eosin staining. Original magnification with 20x and 40x (insets). Scale bar for 100 µm is represented with a line for each panel. (e) CD3, (f) FOXP3 and (g) PD-1 were measured by IHC in a set of TMAs (n = 164) of GEP-NETs, including primary and metastatic tissue. Values represent boxplot of CD3 IHC score and bar graphs of the percentage of samples with positivity for FOXP3 and PD-1 expression in the tumor tissue and in the peritumoral normal tissue. Asterisks indicate significant differences between tumor and peritumoral tissues (p-values for Fisher’s Exact Test: *p < 0.05). (h–k) Immunofluorescence showing different markers in TILs: h) Double immunofluorescence with CD3 (green) and PD-1 (blue). (i) Double immunofluorescence with CD3 (green) and FOXP3 (red). (j) Double immunofluorescence with PD-1 (blue) and FOXP3 (red). (k) Triple immunofluorescence with CD3 (green), PD-1 (blue) and FOXP3 (red). Scale bar for 100 µm is represented with a line for each panel.CC BY · PubMed Central
Figure 3 Expression of PD-1 is associated to increased malignancy in patients with GEP-NETs. (a,e) CD3, (b,f) FOXP3, (c,g) PD-1 and (d,h) PD-L1 were measured by IHC in a set of TMAs (n = 164) of GEP-NETs. Values represent boxplot of CD3 IHC score and bar graphs of the percentage of samples with positivity for PD-1, FOXP3 and PD-L1 expression. (a–d) Samples were classified based on metastases status at diagnosis: patients with metastasis (MET) or without metastasis (No MET). (e–h) Samples were classified based on the disease status at follow-up evaluation: (1) non-residual disease, if a complete resection after surgery had been achieved and no tumor relapse/recurrence was evidenced; (2) stable disease, in cases of residual but non-progressive tumor burden; and (3) progressive disease, if tumor growth or new lesions were detected. The median of follow-up was 4.9 years (p25: 2.6–p75: 8.6 years). Asterisks indicate significant differences (p-value for Fisher’s Exact Test: *p < 0.05).
Figure 3 Expression of PD-1 is associated to increased malignancy in patients with GEP-NETs. (a,e) CD3, (b,f) FOXP3, (c,g) PD-1 and (d,h) PD-L1 were measured by IHC in a set of TMAs (n = 164) of GEP-NETs. Values represent boxplot of CD3 IHC score and bar graphs of the percentage of samples with positivity for PD-1, FOXP3 and PD-L1 expression. (a–d) Samples were classified based on metastases status at diagnosis: patients with metastasis (MET) or without metastasis (No MET). (e–h) Samples were classified based on the disease status at follow-up evaluation: (1) non-residual disease, if a complete resection after surgery had been achieved and no tumor relapse/recurrence was evidenced; (2) stable disease, in cases of residual but non-progressive tumor burden; and (3) progressive disease, if tumor growth or new lesions were detected. The median of follow-up was 4.9 years (p25: 2.6–p75: 8.6 years). Asterisks indicate significant differences (p-value for Fisher’s Exact Test: *p < 0.05).CC BY · PubMed Central
Figure 4 PD-1+ lymphocytes are increased in PBMCs from GEP-NET patients with progressive disease. PBMCs from 32 patients and 32 controls were isolated and incubated with conjugated antibodies directed against CD3, CD4, CD8, CD25, FOXP3 and PD-1. Measurements were made by flow cytometry as stated in ‘Materials and Methods’ and values represent percentage of positive cells for each marker depicted as boxplots. (a–d) Percentage of PD-1+ cells in healthy controls and patients. (e–h) Percentage of PD-1+ cells in controls and patients classified according to disease status in non-residual disease (ND), stable disease (SD) or progressive disease (PD). Asterisks indicate significant differences (p-values for Tukey’s test: *p < 0.05, **p < 0.01, ***p < 0.001).
Figure 4 PD-1+ lymphocytes are increased in PBMCs from GEP-NET patients with progressive disease. PBMCs from 32 patients and 32 controls were isolated and incubated with conjugated antibodies directed against CD3, CD4, CD8, CD25, FOXP3 and PD-1. Measurements were made by flow cytometry as stated in ‘Materials and Methods’ and values represent percentage of positive cells for each marker depicted as boxplots. (a–d) Percentage of PD-1+ cells in healthy controls and patients. (e–h) Percentage of PD-1+ cells in controls and patients classified according to disease status in non-residual disease (ND), stable disease (SD) or progressive disease (PD). Asterisks indicate significant differences (p-values for Tukey’s test: *p < 0.05, **p < 0.01, ***p < 0.001).CC BY · PubMed Central
Figure 5 Simultaneous analysis of peripheral blood and tumor samples. Dot plots of CD3+PD-1+ cells from (a) peripheral blood and (b) tumor specimen from a representative GEP-NET patient. (c) Paired analysis of expression of CD3 + PD-1+ cells in PBMCs and TILs from 3 patients with GEP-NETs. Values represent percentage of CD3 + PD-1+ cells in PBMCs and TILs. P-value from paired T test is shown. (d) Correlation map for the expression of immune markers in TMAs (IHC) and PBMCs (flow cytometry). Values represent the Spearman’s rank correlation coefficient, rho (ρ). Significant negative correlations are shown in orange and significant positive correlations in blue. Color intensity increases with the magnitude of correlation. White color indicates a non-significant correlation.
Figure 5 Simultaneous analysis of peripheral blood and tumor samples. Dot plots of CD3+PD-1+ cells from (a) peripheral blood and (b) tumor specimen from a representative GEP-NET patient. (c) Paired analysis of expression of CD3 + PD-1+ cells in PBMCs and TILs from 3 patients with GEP-NETs. Values represent percentage of CD3 + PD-1+ cells in PBMCs and TILs. P-value from paired T test is shown. (d) Correlation map for the expression of immune markers in TMAs (IHC) and PBMCs (flow cytometry). Values represent the Spearman’s rank correlation coefficient, rho (ρ). Significant negative correlations are shown in orange and significant positive correlations in blue. Color intensity increases with the magnitude of correlation. White color indicates a non-significant correlation.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 4 references

Research works printed but not linked: 36

  1. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25, 9543–9553, https://doi.org/10.1128/MCB.25.21.9543-9553.2005 (2005). · DOI · Paper page
  2. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461, https://doi.org/10.1016/j.ccell.2015.03.001 (2015). · DOI · Paper page
  3. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28, 3167–3175, https://doi.org/10.1200/JCO.2009.26.7609 (2010). · DOI
  4. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32, 1020–1030, https://doi.org/10.1200/JCO.2013.53.0105 (2014). · DOI · Paper page
  5. McDermott, D. F. et al. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol 33, 2013–2020, https://doi.org/10.1200/JCO.2014.58.1041 (2015). · DOI
  6. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562, https://doi.org/10.1038/nature13904 (2014). · DOI
  7. Nowicki, T. S., Hu-Lieskovan, S. & Ribas, A. Mechanisms of Resistance to PD-1 and PD-L1 Blockade. Cancer J 24, 47–53, https://doi.org/10.1097/PPO.0000000000000303 (2018). · DOI
  8. Francisco, L. M., Sage, P. T. & Sharpe, A. H. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 236, 219–242, https://doi.org/10.1111/j.1600-065X.2010.00923.x (2010). · DOI · Paper page
  9. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26, 677–704, https://doi.org/10.1146/annurev.immunol.26.021607.090331 (2008). · DOI · Paper page
  10. Liang, S. C. et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 33, 2706–2716, https://doi.org/10.1002/eji.200324228 (2003). · DOI
  11. Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206, 1327–1337, https://doi.org/10.1084/jem.20082173 (2009). · DOI
  12. Wu, K., Kryczek, I., Chen, L., Zou, W. & Welling, T. H. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res 69, 8067–8075, https://doi.org/10.1158/0008-5472.CAN-09-0901 (2009). · DOI · Paper page
  13. Perrot, I. et al. Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol 178, 2763–2769, https://doi.org/10.4049/jimmunol.178.5.2763 (2007). · DOI
  14. Khan, A. R. et al. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun 6, 5997, https://doi.org/10.1038/ncomms6997 (2015). · DOI
  15. Ostrand-Rosenberg, S., Horn, L. A. & Haile, S. T. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol 193, 3835–3841, https://doi.org/10.4049/jimmunol.1401572 (2014). · DOI
  16. Francisco, L. M. et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206, 3015–3029, https://doi.org/10.1084/jem.20090847 (2009). · DOI
  17. Intlekofer, A. M. & Thompson, C. B. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol 94, 25–39, https://doi.org/10.1189/jlb.1212621 (2013). · DOI
  18. Lee, Y. H., Bae, S. C., Kim, J. H. & Song, G. G. Meta-analysis of genetic polymorphisms in programmed cell death 1. Associations with rheumatoid arthritis, ankylosing spondylitis, and type 1 diabetes susceptibility. Z Rheumatol 74, 230–239, https://doi.org/10.1007/s00393-014-1415-y (2015). · DOI
  19. Gao, J. et al. Meta-analysis of programmed cell death 1 polymorphisms with systemic lupus erythematosus risk. Oncotarget 8, 36885–36897, https://doi.org/10.18632/oncotarget.16378 (2017). · DOI
  20. Chai, S. M., Brown, I. S. & Kumarasinghe, M. P. Gastroenteropancreatic neuroendocrine neoplasms: selected pathology review and molecular updates. Histopathology 72, 153–167, https://doi.org/10.1111/his.13367 (2018). · DOI
  21. Kos-Kudla, B. et al. Current treatment options for gastroenteropancreatic neuroendocrine tumors with a focus on the role of lanreotide. Contemp Oncol (Pozn) 21, 115–122, https://doi.org/10.5114/wo.2017.68619 (2017). · DOI
  22. Yao, J. C. et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26, 3063–3072, https://doi.org/10.1200/JCO.2007.15.4377 (2008). · DOI
  23. Gong, J., Chehrazi-Raffle, A., Reddi, S. & Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6, 8, https://doi.org/10.1186/s40425-018-0316-z (2018). · DOI
  24. Lamarca, A. et al. PD-L1 expression and presence of TILs in small intestinal neuroendocrine tumours. Oncotarget 9, 14922–14938, https://doi.org/10.18632/oncotarget.24464 (2018). · DOI
  25. Dong, H., Zhu, G., Tamada, K. & Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5, 1365–1369, https://doi.org/10.1038/70932 (1999). · DOI · Paper page
  26. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8, 793–800, https://doi.org/10.1038/nm730 (2002). · DOI · Paper page
  27. Yamazaki, T. et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169, 5538–5545, https://doi.org/10.4049/jimmunol.169.10.5538 (2002). · DOI
  28. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20, 5064–5074, https://doi.org/10.1158/1078-0432.CCR-13-3271 (2014). · DOI · Paper page
  29. Fan, Y. et al. Prognostic value of PD-L1 and PD-1 expression in pulmonary neuroendocrine tumors. Onco Targets Ther 9, 6075–6082, https://doi.org/10.2147/OTT.S115054 (2016). · DOI
  30. Tsuruoka, K. et al. PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer 108, 115–120, https://doi.org/10.1016/j.lungcan.2017.03.006 (2017). · DOI
  31. Schultheis, A. M. et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 51, 421–426, https://doi.org/10.1016/j.ejca.2014.12.006 (2015). · DOI
  32. Kim, S. T. et al. The Impact of PD-L1 Expression in Patients with Metastatic GEP-NETs. J Cancer 7, 484–489, https://doi.org/10.7150/jca.13711 (2016). · DOI
  33. Cavalcanti, E., Armentano, R., Valentini, A. M., Chieppa, M. & Caruso, M. L. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis 8, e3004, https://doi.org/10.1038/cddis.2017.401 (2017). · DOI
  34. Zheng, H. et al. Expression of PD-1 on CD4+ T cells in peripheral blood associates with poor clinical outcome in non-small cell lung cancer. Oncotarget 7, 56233–56240, https://doi.org/10.18632/oncotarget.9316 (2016). · DOI
  35. Oberg, K. et al. ENETS Consensus Guidelines for Standard of Care in Neuroendocrine Tumours: Biochemical Markers. Neuroendocrinology 105, 201–211, https://doi.org/10.1159/000472254 (2017). · DOI
  36. Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (Springer-Verlag New York, 2009). · DOI · Paper page

Cited by

Sorted by citations

See all 49

Metadata

Authors
Sampedro-Núñez, M., Serrano-Somavilla, A., Adrados, M., Cameselle-Teijeiro, J. M., Blanco-Carrera, C., Cabezas-Agricola, J. M., Martínez-Hernández, R., Martín-Pérez, E., Muñoz de Nova, J. L., Díaz, J. Á., García-Centeno, R., Caneiro-Gómez, J., Abdulkader, I., González-Amaro, R., & Marazuela, M.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-12-13
Volume
8
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-018-36129-1
PMC
PMC6292913
Cited by
49
References
4
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Analysis of expression of the PD-1/PD-L1 immune checkpoint system and its prognostic impact in gastroenteropancreatic neuroendocrine tumors. https://app.cochat.ai/papers/10.1038/s41598-018-36129-1
The paper
Sampedro-Núñez, M., Serrano-Somavilla, A., Adrados, M., Cameselle-Teijeiro, J. M., Blanco-Carrera, C., Cabezas-Agricola, J. M., Martínez-Hernández, R., Martín-Pérez, E., Muñoz de Nova, J. L., Díaz, J. Á., García-Centeno, R., Caneiro-Gómez, J., Abdulkader, I., González-Amaro, R., & Marazuela, M. (2018). Analysis of expression of the PD-1/PD-L1 immune checkpoint system and its prognostic impact in gastroenteropancreatic neuroendocrine tumors. Scientific Reports. https://doi.org/10.1038/s41598-018-36129-1