Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions
Journal article, 2021

Background & Aims:
Virus-specific T cell dysfunction is a common feature of HBV-related hepatocellular carcinoma (HBV-HCC). Conventional T (ConT) cells can be redirected towards viral antigens in HBV-HCC when they express an HBV-specific receptor; however, their efficacy can be impaired by liver-specific physical and metabolic features. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the liver and can elicit potent intrahepatic effector functions. Here, we engineered ConT and MAIT cells to kill HBV expressing hepatoma cells and compared their functional properties.
Methods:
Donor-matched ConT and MAIT cells were engineered to express an HBV-specific T cell receptor (TCR). Cytotoxicity and hepatocyte homing potential were investigated using flow cytometry, real-time killing assays, and confocal microscopy in 2D and 3D HBV-HCC cell models. Major histocompatibility complex (MHC) class I-related molecule (MR1)-dependent and MR1-independent activation was evaluated in an Escherichia coli THP-1 cell model and by IL-12/IL-18 stimulation, respectively.
Results:
HBV TCR-MAIT cells demonstrated polyfunctional properties (CD107a, interferon [IFN] γ, tumour necrosis factor [TNF], and IL-17A) with strong HBV target sensitivity and liver-homing chemokine receptor expression when compared with HBV TCR-ConT cells. TCR-mediated lysis of hepatoma cells was comparable between the cell types and augmented in the presence of inflammation. Coculturing with HBV+ target cells in a 3D microdevice mimicking aspects of the liver microenvironment demonstrated that TCR-MAIT cells migrate readily towards hepatoma targets. Expression of an ectopic TCR did not affect the ability of the MAIT cells to be activated via MR1-presented bacterial antigens or IL-12/IL-18 stimulation.
Conclusions:
HBV TCR-MAIT cells demonstrate anti-HBV functions without losing their endogenous antimicrobial mechanisms or hepatotropic features. Our results support future exploitations of MAIT cells for liver-directed immunotherapies. Lay summary: Chronic HBV infection is a leading cause of liver cancer. T cell receptor (TCR)-engineered T cells are patients’ immune cells that have been modified to recognise virus-infected and/or cancer cells. Herein, we evaluated whether mucosal-associated invariant T cells, a large population of unconventional T cells in the liver, could recognise and kill HBV infected hepatocytes when engineered with an HBV-specific TCR. We show that their effector functions may exceed those of conventional T cells currently used in the clinic, including antimicrobial properties and chemokine receptor profiles better suited for targeting liver tumours.

MAIT cells

HCC

TCR-T cells

HBV

Adoptive cell transfer

Author

Katie Healy

Karolinska Institutet

Andrea Pavesi

Institute of Molecular and Cell Biology

Tiphaine Parrot

Karolinska Institutet

Michał J. Sobkowiak

Karolinska Institutet

Susanne Reinsbach

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology, CSBI

Haleh Davanian

Karolinska Institutet

Anthony T. Tan

Duke-NUS Medical School Singapore

Soo Aleman

Karolinska University Hospital

Karolinska Institutet

Johan K Sandberg

Karolinska Institutet

Antonio Bertoletti

Duke-NUS Medical School Singapore

Margaret Sällberg Chen

Karolinska Institutet

JHEP Reports

25895559 (eISSN)

Vol. 3 4 100318

Subject Categories

Immunology

Cell and Molecular Biology

Immunology in the medical area

DOI

10.1016/j.jhepr.2021.100318

PubMed

34377970

More information

Latest update

7/30/2021