Melo, Ashanty M. and O'Brien, Aisling M. and Phelan, James J. and Kennedy, Susan A. and Wood, Nicole A.W. and Veerapen, Natacha and Besra, Gurdyal S. and Clarke, Niamh E. and Foley, Emma K. and Ravi, Akshaya and MacCarthy, Finbar and O'Toole, Dermot and Ravi, Narayamasami and Reynolds, John V. and Conroy, Melissa J. and Hogan, Andrew and O'Sullivan, Jacintha and Dunne, Margaret R. (2019) Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma. Frontiers in Immunology, 10 (1580). ISSN 1664-3224

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Abstract

Oesophageal adenocarcinoma (OAC) is an aggressive malignancy with poor prognosis, and incidence is increasing rapidly in the Western world. Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites and kill infected cells, yet their role in OAC is unknown. We aimed to elucidate the role of MAIT cells during cancer development by characterizing the frequency, phenotype, and function of MAIT cells in human blood and tissues, from OAC and its pre-malignant inflammatory condition Barrett’s oesophagus (BO). Blood and tissues were phenotyped by flow cytometry and conditioned media from explanted tissue was used to model the effects of the tumor microenvironment on MAIT cell function. Associations were assessed between MAIT cell frequency, circulating inflammatory markers, and clinical parameters to elucidate the role of MAIT cells in inflammation driven cancer. MAIT cells were decreased in BO and OAC blood compared to healthy controls, but were increased in oesophageal tissues, compared to BO-adjacent tissue, and remained detectable after neo-adjuvant treatment. MAIT cells in tumors expressed CD8, PD-1, and NKG2A but lower NKG2D than BO cohorts. MAIT cells produced less IFN-γ and TNF-α in the presence of tumor-conditioned media. OAC cell line viability was reduced upon exposure to expanded MAIT cells. Serum levels of chemokine IP-10 were inversely correlated with MAIT cell frequency in both tumors and blood. MAIT cells were higher in the tumors of node-negative patients, but were not significantly associated with other clinical parameters. This study demonstrates that OAC tumors are infiltrated by MAIT cells, a type of CD8 T cell featuring immune checkpoint expression and cytotoxic potential. These findings may have implications for immunotherapy and immune scoring approaches.

Item Type:	Article
Additional Information:	Funding: This study was funded by an Irish Research Council fellowship GOIPD/2014/314 (MRD). EF was supported by the Cancer Research of the Oesophagus and Stomach at St James’s Hospital (CROSS) charity. NC was supported by the Oesophageal Cancer Fund (OCF). NW and AH were supported by a grant from the National Children’s Research Centre (NCRC). Cite as: Melo AM, O’Brien AM, Phelan JJ, Kennedy SA, Wood NAW, Veerapen N, Besra GS, Clarke NE, Foley EK, Ravi A, MacCarthy F, O’Toole D, Ravi N, Reynolds JV, Conroy MJ, Hogan AE, O’Sullivan J and Dunne MR (2019) Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma. Front. Immunol. 10:1580. doi: 10.3389/fimmu.2019.01580
Keywords:	MAIT cells; oesophageal adenocarcinoma; Barrett’s Oesophagus; cancer immunology; tumor microenvironment; PD-1;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	13972
Identification Number:	https://doi.org/10.3389/fimmu.2019.01580
Depositing User:	Andrew Hogan
Date Deposited:	08 Feb 2021 16:44
Journal or Publication Title:	Frontiers in Immunology
Publisher:	Frontiers Media
Refereed:	Yes
Funders:	Irish Research Council (IRC), Cancer Research of the Oesophagus and Stomach at St James’s Hospital (CROSS), Oesophageal Cancer Fund (OCF), National Children’s Research Centre (NCRC)
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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