Neuroendocrine tumours and their microenvironment.

Content Provider	Europe PMC
Author	de Hosson, Lotte D. Takkenkamp, Tim J. Kats-Ugurlu, Gursah Bouma, Grietje Bulthuis, Marian de Vries, Elisabeth G. E. van Faassen, Martijn Kema, Ido P. Walenkamp, Annemiek M. E.
Abstract	Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in < 1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed α-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses.Electronic supplementary materialThe online version of this article (10.1007/s00262-020-02556-1) contains supplementary material, which is available to authorized users.
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ISSN	03407004
Journal	Cancer Immunology, Immunotherapy [Cancer Immunol Immunother]
Volume Number	69
DOI	10.1007/s00262-020-02556-1
PubMed Central reference number	PMC7347684
Issue Number	8
PubMed reference number	32270230
e-ISSN	14320851
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2020-04-08
Publisher Place	Berlin/Heidelberg
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2020
Subject Keyword	Neuroendocrine tumours Programmed death-ligand-1 Indoleamine 2,3-dioxygenase Tryptophan 2,3-dioxygenase T-cells Immune microenvironment
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Cancer Research Immunology Oncology