Research Papers:

PD-L1 expression and presence of TILs in small intestinal neuroendocrine tumours

Angela Lamarca, Daisuke Nonaka, Wolfgang Breitwieser, Garry Ashton, Jorge Barriuso, Mairéad G. McNamara, Sharzad Moghadam, Jane Rogan, Wasat Mansoor, Richard A. Hubner, Christopher Clark, Bipasha Chakrabarty and Juan W. Valle _

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Oncotarget. 2018; 9:14922-14938. https://doi.org/10.18632/oncotarget.24464

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Angela Lamarca1, Daisuke Nonaka2,3, Wolfgang Breitwieser4, Garry Ashton5, Jorge Barriuso1,3, Mairéad G. McNamara1,3, Sharzad Moghadam5, Jane Rogan5, Wasat Mansoor1, Richard A. Hubner1, Christopher Clark4, Bipasha Chakrabarty2 and Juan W. Valle1,3

1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

2Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK

3Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

4Molecular Biology Core Facility, Cancer Research UK Manchester Institute, Manchester, UK

5Manchester Cancer Research Centre (MCRC) BioBank, University of Manchester, Manchester, UK

Correspondence to:

Juan W. Valle, email: [email protected], [email protected]

Keywords: PD-L1; tumour infiltrating lymphocytes; neuroendocrine; immunotherapy; treatment

Received: November 22, 2017     Accepted: February 03, 2018     Epub: February 12, 2018     Published: March 13, 2018


Background: The extent of resistance to immune surveillance in patients with well-differentiated (Wd) (grade 1/2) small-intestinal neuroendocrine tumours (Si-NETs) is unknown.

Methods: Patients diagnosed with Wd Si-NETs (excluding appendix, which are considered to have a different biology to other midgut NETs) were eligible. Tumoural programmed death (PD)-ligand(L) 1 (PD-L1)/PD-L2/PD-1 and tumour infiltrating lymphocytes (TILs) [presence and phenotype] were analysed in archival tissue by immunohistochemistry (IHC); reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for confirmation of IHC results.

Results: Of 109 patients screened, 62 were eligible: 54.8% were male; median age was 63.7 years (95%-CI 59.7-67.2); disease stage II: 4.8%, III: 40.3% and IV: 54.8%; 41.9% were functional. Analysed samples (67.1% from primary tumours, 32.9% from metastases) were of grade 1 (67.1%) or 2 (32.86%) with a median Ki-67 of 2%. From the total of 62 eligible patients, 70 and 63 samples were suitable for IHC and RT-qPCR analysis, respectively. PD-L1 expression within tumour cells and TILs were identified in 12.8% and 24.3% of samples respectively; 30% of samples showed PD-L1 expression within tumour cells and/or TILs. PD-1 was present in TILs in 22.8% of samples. Majority of samples showed significant presence of CD4+ (focal 42.86%; moderate 2.86%) and CD8+ (focal 92.86%; moderate 4.29%) TILs. IHC findings were confirmed with RT-qPCR; which showed higher expression levels of PD-L1 (p-value 0.007) and PD-1 (p-value 0.001) in samples positive for IHC compared to negative-IHC.

Conclusions: Thirty-percent of patients express PD-L1 within tumour cells and/or TILs. Identification of presence of TILs was also significant and warrant the investigation of immunotherapy in this setting.

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