Antitumor immune response is associated with favorable survival in GEP-NEN G3

in Endocrine-Related Cancer
Authors:
Vivian Rosery Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Vivian Rosery in
Current site
Google Scholar
PubMed Close
,
Henning Reis Institute of Pathology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Henning Reis in
Current site
Google Scholar
PubMed Close
,
Konstantinos Savvatakis Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by Konstantinos Savvatakis in
Current site
Google Scholar
PubMed Close
,
Bernd Kowall Center of Clinical Epidemiology, Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University Duisburg-Essen, Essen, Germany

Search for other papers by Bernd Kowall in
Current site
Google Scholar
PubMed Close
,
Martin Stuschke Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

Search for other papers by Martin Stuschke in
Current site
Google Scholar
PubMed Close
,
Andreas Paul German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Search for other papers by Andreas Paul in
Current site
Google Scholar
PubMed Close
,
Alexander Dechêne Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Internal Medicine 6, Paracelsus Medical University, Nürnberg, Germany

Search for other papers by Alexander Dechêne in
Current site
Google Scholar
PubMed Close
,
JiaJin Yang Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by JiaJin Yang in
Current site
Google Scholar
PubMed Close
,
Ben Zhao Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by Ben Zhao in
Current site
Google Scholar
PubMed Close
,
Arianna Borgers Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by Arianna Borgers in
Current site
Google Scholar
PubMed Close
,
Stefan Kasper Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

Search for other papers by Stefan Kasper in
Current site
Google Scholar
PubMed Close
,
Martin Schuler Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

Search for other papers by Martin Schuler in
Current site
Google Scholar
PubMed Close
,
Phyllis F Cheung Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

Search for other papers by Phyllis F Cheung in
Current site
Google Scholar
PubMed Close
, and
Jens T Siveke Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

Search for other papers by Jens T Siveke in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-8772-4778

Correspondence should be addressed to P F Cheung or J T Siveke: fung-yi.cheung@uk-essen.de or jens.siveke@uk-essen.de
DOI:
https://doi.org/10.1530/ERC-21-0223
Volume/Issue:
Volume 28: Issue 10
Article Type:
Research Article
Page Range:
683–693
Online Publication Date:
02 Sep 2021
Copyright:
© Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

The tumor immune microenvironment (TME) represents a key determinant for responses to cancer treatment. However, the immune phenotype of highly proliferative gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is still largely elusive. In this retrospective study, we characterized the TME of high-grade (G3, Ki-67 > 20%) GEP-NEN. We analyzed formalin-fixed paraffin-embedded samples from 37 patients with GEP-NEN G3 by immunohistochemistry and multiplex immunofluorescence to address the abundance and spatial interaction of relevant immune subsets. We focused on the expression of immune checkpoint molecules PD-1 and PD-L1, the cytotoxic T-cell marker CD8, and the tumor-associated macrophage marker CD206. Findings were correlated with overall survival (OS) from the date of a cancer diagnosis. Patients with PD-L1-positive tumors (CPS ≥ 1) and intense PD-1+CD8+ immune cell infiltration showed the most favorable median OS. Multiplex immunofluorescence staining of ten representative tissue samples illustrated intratumoral heterogeneity of PD-L1 expression. Dense PD-1+CD8+ immune cell infiltrates were observed in PD-L1-positive tumor regions but not in PD-L1-negative regions. Proximity analysis revealed a spatial interaction between PD-1+CD8+ cells and PD-L1-positive cells. Our data suggest a pre-existing antitumor immune response in the TME in a subgroup of GEP-NEN G3. This supports a targeted clinical exploration of immunotherapeutic approaches.

Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 679 14 0
PDF Downloads 474 23 0

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2021
Page(s):
11
Received Date:
09 Jul 2021
Accepted Date:
06 Aug 2021
Print Publication Date:
01 Oct 2021
Online Publication Date:
02 Sep 2021
Keywords:
PD-1; PD-L1; checkpoint molecule; immune infiltrate; spatial imaging; gastroenteropancreatic neuroendocrine neoplasm

  • Bosch F, Bruwer K, Altendorf-Hofmann A, Auernhammer CJ, Spitzweg C, Westphalen CB, Boeck S, Schubert-Fritschle G, Werner J & Heinemann V et al.2019 Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia. Endocrine-Related Cancer 26 293–301. (https://doi.org/10.1530/ERC-18-0494)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bosman FT, Carneiro F, Hruban RH & Theise ND 2010 WHO Classification of Tumours of the Digestive Systems. Lyon, France: International Agengy for Research on Cancer.

  • Busse A, Mochmann LH, Spenke C, Arsenic R, Briest F, Johrens K, Lammert H, Sipos B, Kuhl AA & Wirtz R et al.2020 Immunoprofiling in neuroendocrine neoplasms unveil immunosuppressive microenvironment. Cancers 12 3448.(https://doi.org/10.3390/cancers12113448)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cavalcanti E, Armentano R, Valentini AM, Chieppa M & Caruso ML 2017 Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death and Disease 8 e3004. (https://doi.org/10.1038/cddis.2017.401)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fan Y, Ma K, Wang C, Ning J, Hu Y, Dong D, Dong X, Geng Q, Li E & Wu Y 2016 Prognostic value of PD-L1 and PD-1 expression in pulmonary neuroendocrine tumors. OncoTargets and Therapy 9 6075–6082. (https://doi.org/10.2147/OTT.S115054)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fottner C, Apostolidis L, Ferrata M, Krug S, Michl P, Schad A, Roth W, Jaeger D, Galle PR & Weber MM 2019 A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC). Journal of Clinical Oncology 37 4103–4103. (https://doi.org/10.1200/JCO.2019.37.15_suppl.4103)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M & Cwikla JB et al.2016 Enets consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 103 186–1 94. (https://doi.org/10.1159/000443172)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Giraldo NA, Nguyen P, Engle EL, Kaunitz GJ, Cottrell TR, Berry S, Green B, Soni A, Cuda JD & Stein JE et al.2018 Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab. Journal for ImmunoTherapy of Cancer 6 99. (https://doi.org/10.1186/s40425-018-0404-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hanahan D & Weinberg RA 2011 Hallmarks of cancer: the next generation. Cell 144 646–6 74. (https://doi.org/10.1016/j.cell.2011.02.013)

  • Hofman P, Badoual C, Henderson F, Berland L, Hamila M, Long-Mira E, Lassalle S, Roussel H, Hofman V & Tartour E et al.2019 Multiplexed immunohistochemistry for molecular and immune profiling in lung cancer-just about ready for prime-time? Cancers 11 283. (https://doi.org/10.3390/cancers11030283)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Nishio M, Okumura S & Ishikawa Y 2017 Relationship of tumor PD-L1 (CD274) expression with lower mortality in lung high-grade neuroendocrine tumor. Cancer Medicine 6 2347–2356. (https://doi.org/10.1002/cam4.1172)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kasajima A, Ishikawa Y, Iwata A, Steiger K, Oka N, Ishida H, Sakurada A, Suzuki H, Kameya T & Konukiewitz B et al.2018 Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors. Endocrine-Related Cancer 25 339–350. (https://doi.org/10.1530/ERC-17-0427)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kather JN, Suarez-Carmona M, Charoentong P, Weis CA, Hirsch D, Bankhead P, Horning M, Ferber D, Kel I & Herpel E et al.2018 Topography of cancer-associated immune cells in human solid tumors. eLife 7 e36967. (https://doi.org/10.7554/eLife.36967)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim ST, Ha SY, Lee S, Ahn S, Lee J, Park SH, Park JO, Lim HY, Kang WK & Kim KM et al.2016 The impact of PD-L1 expression in patients with metastatic GEP-NETs. Journal of Cancer 7 484–48 9. (https://doi.org/10.7150/jca.13711)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C & Nagrial A et al.2020 Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clinical Cancer Research 26 4454–4459. (https://doi.org/10.1158/1078-0432.CCR-20-0621)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kulangara K, Zhang N, Corigliano E, Guerrero L, Waldroup S, Jaiswal D, Ms MJ, Shah S, Hanks D & Wang J et al.2019 Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Archives of Pathology and Laboratory Medicine 143 330–337.(https://doi.org/10.5858/arpa.2018-0043-OA)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lloyd RV, Osamura RY, Klöppel G & Rosai J 2017 WHO Classification of Tumors of Endocrine Organs. Lyon, France: International Agengy for Research on Cancer.

  • Maggio I, Manuzzi L, Lamberti G, Ricci AD, Tober N & Campana D 2020 Landscape and future perspectives of immunotherapy in neuroendocrine neoplasia. Cancers 12 832. (https://doi.org/10.3390/cancers12040832)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McNamara MG, Scoazec JY & Walter T 2020 Extrapulmonary poorly differentiated NECs, including molecular and immune aspects. Endocrine-Related Cancer 27 R219–R238. (https://doi.org/10.1530/ERC-19-0483)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA & WHO Classification of Tumours Editorial Board 2020 The 2019 WHO classification of tumours of the digestive system. Histopathology 76 182–188.(https://doi.org/10.1111/his.13975)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Oktay E, Yalcin GD, Ekmekci S, Kahraman DS, Yalcin A, Degirmenci M, Dirican A, Altin Z, Ozdemir O & Surmeli Z et al.2019 Programmed cell death ligand-1 expression in gastroenteropancreatic neuroendocrine tumors. Journal of BUON 24 779–790.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, Fontaine A, Shah MH, Kasi A & Baghdadi TA et al.2020 A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (Dart SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clinical Cancer Research 26 2290–2296. (https://doi.org/10.1158/1078-0432.CCR-19-3356)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roberts JA, Gonzalez RS, Das S, Berlin J & Shi C 2017 Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy. Human Pathology 70 49–54. (https://doi.org/10.1016/j.humpath.2017.10.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG & Ohrling K et al.2013 Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the Nordic NEC study. Annals of Oncology 24 152–1 60. (https://doi.org/10.1093/annonc/mds276)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sorbye H, Strosberg J, Baudin E, Klimstra DS & Yao JC 2014 Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 120 2814–2 82 3. (https://doi.org/10.1002/cncr.28721)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sorbye H, Baudin E, Borbath I, Caplin M, Chen J, Cwikla JB, Frilling A, Grossman A, Kaltsas G & Scarpa A et al.2019 Unmet needs in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Neuroendocrinology 108 54–62. (https://doi.org/10.1159/000493318)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R, Bergsland E, Shah M, Fakih M & Takahashi S et al.2020 Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II keynote-158 study. Clinical Cancer Research 26 2124–2130. (https://doi.org/10.1158/1078-0432.CCR-19-3014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Weber MM & Fottner C 2018 Immune checkpoint inhibitors in the treatment of patients with neuroendocrine neoplasia. Oncology Research and Treatment 41 306–312. (https://doi.org/10.1159/000488996)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wei SC, Duffy CR & Allison JP 2018 Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery 8 1069–1086. (https://doi.org/10.1158/2159-8290.CD-18-0367)

    • PubMed
    • Search Google Scholar
    • Export Citation