TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8 <sup>+</sup> T Cells in Hepatocellular Carcinoma

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Abstract

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 PD1 ^high CD8 ⁺ TILs. PD1 ^high 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 PD1 ^high CD8 ⁺ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8 ⁺ TILs from tumors enriched for PD1 ^int 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.

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Author and article information

Contributors

Dave Sprengers

Journal

Journal ID (nlm-ta): Cell Mol Gastroenterol Hepatol

Journal ID (iso-abbrev): Cell Mol Gastroenterol Hepatol

Title: Cellular and Molecular Gastroenterology and Hepatology

Publisher: Elsevier

ISSN (Electronic): 2352-345X

Publication date Collection: 2021

Publication date (Electronic): 27 March 2021

Volume: 12

Issue: 2

Pages: 443-464

Affiliations

[1 ]Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

[2 ]Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

[3 ]Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

[4 ]Department of Gastroenterology and Hepatology, Amsterdam UMC location AMC, Amsterdam, the Netherlands

[5 ]Department of Pathology, Amsterdam UMC location AMC, Amsterdam, the Netherlands

[6 ]Department of Surgery, Amsterdam UMC location AMC, Amsterdam, the Netherlands

[7 ]Department of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands

Author notes

[∗ ] Correspondence Address correspondence to: Dave Sprengers, MD, PhD, Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. fax: +31 10 7030352. d.sprengers@ 123456erasmusmc.nl

[b]

Authors share co-senior authorship.

Article

Publisher Item ID: S2352-345X(21)00055-2

DOI: 10.1016/j.jcmgh.2021.03.003

PMC ID: 8255944

PubMed ID: 33781741

SO-VID: 0e7c093a-51d2-4e6f-b1f7-501ba76c5159

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 2 June 2020

Date accepted : 2 March 2021

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