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

Autor: Haleh Davanian, Margaret Chen, Soo Aleman, Anthony T. Tan, Katie Healy, Antonio Bertoletti, Andrea Pavesi, Tiphaine Parrot, Johan K. Sandberg, Susanne E Reinsbach, Michał J. Sobkowiak
Rok vydání: 2021
Předmět:
CAR
chimeric antigen receptor
Adoptive cell transfer
VLA-4
very late antigen-4
MAIT
mucosal-associated invariant T
TNF
tumour necrosis function
CCR
CC chemokine receptor
RC799-869
VCAM-1
vascular cell adhesion molecule-1
TCR-T cells
APC
allophycocyanin
HBV
Immunology and Allergy
Cytotoxic T cell
MFI
mean fluorescence intensity
FMO
fluorescence minus one
HCC
CXCR
CXC chemokine receptor
biology
TCR
T cell receptor
Gastroenterology
5-OP-RU
5-(2-oxopropylideneamino)-6-d-ribitylaminouracil
Diseases of the digestive system. Gastroenterology
PMA
phorbol myristate acetate
MR1
MHC class I-related molecule
RT
room temperature
Research Article
PBMC
peripheral blood mononuclear cell
FSC
forward scatter
MAIT cells
Human leukocyte antigen
Major histocompatibility complex
DCI
dead cell index
Immune system
IR
irrelevant peptide
UMAP
Uniform Manifold Approximation and Projection
Internal Medicine
MHC
major histocompatibility complex
IFN
interferon
CXCL
chemokine (CXC) ligand
Hepatology
HLA
human leukocyte antigen
T-cell receptor
ConT
conventional T
PE
phycoerythrin
digestive system diseases
SSC
side scatter
Cancer cell
biology.protein
Cancer research
HCC
hepatocellular carcinoma
CC chemokine receptors
Zdroj: JHEP Reports, Vol 3, Iss 4, Pp 100318-(2021)
JHEP Reports
ISSN: 2589-5559
DOI: 10.1016/j.jhepr.2021.100318
Popis: 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.
Graphical abstract
Highlights • Mucosal-associated invariant T (MAIT) cells expanded in vitro can be engineered to kill HBV antigen-presenting hepatoma cells. • MAIT cells produce IL-17A upon encountering their HBV targets, a functional property not observed in conventional T cells currently used in immunotherapy. • HBV-specific MAIT cells migrate readily towards liver targets in a 3D microfluidics system. • Co-expression of an HBV-specific TCR does not affect the ability of MAIT cells to respond to their physiological stimuli.
Databáze: OpenAIRE
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