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Programmed cell death-1 receptor-mediated regulation of Tbet+NK1.1- innate lymphoid cells within the tumor microenvironment

Lookup NU author(s): Jing Lim, Grace Mallett, Dr David McDonald, Dr Gill Hulme, Dr Stephanie Laba, Megan Payne, Warren Patterson, Michael Alexander, Dr Jonathan Coxhead, Dr Andrew Filby, Professor Ruth Plummer, Professor Penny Lovat, Dr Eugene Healy, Dr Shoba AmarnathORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1- ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1- ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet+NK1.1- ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet+NK1.1- ILCs expressed significantly increased IFN╬│ and granzyme B and K. Furthermore, PD-1-deficient Tbet+NK1.1- ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet+NK1.1- ILCs within the TME.


Publication metadata

Author(s): Lim JX, Lai CY, Mallett GE, McDonald D, Hulme G, Laba S, Shapanis A, Payne M, Patterson W, Alexander M, Coxhead J, Filby A, Plummer R, Lovat PE, Sciume G, Healy E, Amarnath S

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2023

Volume: 120

Issue: 18

Print publication date: 02/05/2023

Online publication date: 25/04/2023

Acceptance date: 07/03/2023

Date deposited: 16/05/2023

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.2216587120

DOI: 10.1073/pnas.2216587120

PubMed id: 37098069


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Funding

Funder referenceFunder name
1953078
MFAG-21311
LF-AW_EMEA-19-400028
NC/W002043/1
MR/T015586/1
SBF003/1129

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