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Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumours

Vesely, Clare; Wong, Yien Ning Sophia; Childs, Alexa; Akarca, Ayse U; Dhami, Pawan; Vaikkinen, Heli; Conde, Lucia; ... Meyer, Tim; + view all (2022) Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumours. Clinical Cancer Research 10.1158/1078-0432.CCR-21-4203. (In press). Green open access

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Abstract

BACKGROUND: The immune tumour microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumours (siNET) have not been fully defined. METHODS: Herein, we studied 40 patients with primary and synchronous metastatic siNETs , and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. Additionally, matched FFPE tissue was obtained for multi-parametric immunohistochemistry (IHC) to determine the relative abundance and distribution of T-cell infiltrate. Tumour mutational burden (TMB) was also assessed and correlated with immune infiltration. RESULTS: Effector tumour infiltrating lymphocytes had a higher expression of PD-1 in the tumour microenvironment compared to the periphery. Additionally, CD8+ tumour infiltrating lymphocytes had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 and higher levels of PD-1 expression compared to normal tissue. IHC revealed that the majority of cases have {less than or equal to}10% intratumoural T cells but a higher number of peritumoural T cells, demonstrating an "exclusion" phenotype. Finally, we confirmed that siNETs have a low TMB compared to other tumour types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio. CONCLUSIONS: Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit "excluded" T cells into the tumour microenvironment to treat patients with siNETs.

Type: Article
Title: Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumours
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-21-4203
Publisher version: https://doi.org/10.1158/1078-0432.CCR-21-4203
Language: English
Additional information: © The Author 2022. This work is licensed under a Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
URI: https://discovery.ucl.ac.uk/id/eprint/10145970
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