TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8

Autor: Zhouhong, Ge, Guoying, Zhou, Lucia, Campos Carrascosa, Erik, Gausvik, Patrick P C, Boor, Lisanne, Noordam, Michael, Doukas, Wojciech G, Polak, Türkan, Terkivatan, Qiuwei, Pan, R Bart, Takkenberg, Joanne, Verheij, Joris I, Erdmann, Jan N M, IJzermans, Maikel P, Peppelenbosch, Jaco, Kraan, Jaap, Kwekkeboom, Dave, Sprengers
Rok vydání: 2020
Předmět:
Male
PMA
phorbol 12-myristate 13-acetate
Carcinoma
Hepatocellular
TIGIT
Programmed Cell Death 1 Receptor
Antigen-Presenting Cells
Down-Regulation
chemical and pharmacologic phenomena
TCF1
transcription factor 1
CD8-Positive T-Lymphocytes
SEM
standard error of the mean
T-Lymphocytes
Regulatory
cDC
conventional dendritic cells
AFP
alpha fetoprotein
LAG3
lymphocyte-activation gene 3
Lymphocytes
Tumor-Infiltrating
MFI
median fluorescent intensity
Antigens
CD
HMGB Proteins
TFL
tumor-free liver tissue
TMA
tissue microarray
Humans
IFN
interferon
TIM3
T-cell immunoglobulin and mucin-domain containing-3
Receptors
Immunologic
HCC
Aged
Cell Proliferation
Original Research
TNF
tumor necrosis factor
Thymocytes
Liver Neoplasms
hemic and immune systems
Hep G2 Cells
PD1
programmed cell death protein 1
Up-Regulation
TIGIT
T-cell immune receptor with Ig and ITIM domains
Treg
regulatory T cells
TOX
CD226
PD-L1
programmed death-ligand 1
TIL
tumor-infiltrating leukocyte
APC
antigen-presenting cell
Female
Immunotherapy
HCC
hepatocellular carcinoma
TOX
thymocyte selection-associated high mobility group box protein
Zdroj: Cellular and Molecular Gastroenterology and Hepatology
ISSN: 2352-345X
Popis: Background & Aims TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). Methods Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. Results TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1high CD8+ TILs. PD1high TIGIT+ CD8+ TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8+ TILs from tumors with PD1high CD8+ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8+ TILs from tumors enriched for PD1int CD8+ TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8+ TILs compared with single PD1 blockade. Conclusions Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8+ TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.
Graphical abstract
Databáze: OpenAIRE
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