TY - JOUR
T1 - TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma
AU - Ge, Zhouhong
AU - Zhou, Guoying
AU - Campos Carrascosa, Lucia
AU - Gausvik, Erik
AU - Boor, Patrick P C
AU - Noordam, Lisanne
AU - Doukas, Michael
AU - Polak, Wojciech G
AU - Terkivatan, Türkan
AU - Pan, Qiuwei
AU - Takkenberg, R Bart
AU - Verheij, Joanne
AU - Erdmann, Joris I
AU - IJzermans, Jan N M
AU - Peppelenbosch, Maikel P
AU - Kraan, Jaco
AU - Kwekkeboom, Jaap
AU - Sprengers, Dave
N1 - Funding Information: Funding Supported by the China Scholarship Council , which provided a PhD fellowship grant to Zhouhong Ge (number 201606230253). Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Aged
KW - Antigen-Presenting Cells/immunology
KW - Antigens, CD/metabolism
KW - CD8-Positive T-Lymphocytes/immunology
KW - Carcinoma, Hepatocellular/immunology
KW - Cell Proliferation
KW - Down-Regulation
KW - Female
KW - HMGB Proteins/metabolism
KW - Hep G2 Cells
KW - Humans
KW - Liver Neoplasms/immunology
KW - Lymphocytes, Tumor-Infiltrating/immunology
KW - Male
KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors
KW - Receptors, Immunologic/antagonists & inhibitors
KW - T-Lymphocytes, Regulatory/immunology
KW - Thymocytes/immunology
KW - Up-Regulation
UR - http://www.scopus.com/inward/record.url?scp=85112657289&partnerID=8YFLogxK
U2 - 10.1016/j.jcmgh.2021.03.003
DO - 10.1016/j.jcmgh.2021.03.003
M3 - Article
C2 - 33781741
SN - 2352-345X
VL - 12
SP - 443
EP - 464
JO - Cellular and Molecular Gastroenterology and Hepatology
JF - Cellular and Molecular Gastroenterology and Hepatology
IS - 2
ER -