- •TOX promotes CD8+ T cell exhaustion in hepatocellular carcinoma.
- •TOX impairs CD8+ T cell antitumor function and response to anti-PD1 therapy.
- •TOX increases surface PD1 level of tumor-infiltrating CD8+ T cells.
- •TOX in peripheral CD8+ T cells is an unfavorable prognostic factor for hepatocellular carcinoma.
Background & Aims
The thymocyte selection-associated high mobility group box protein (TOX) plays a vital role in T cell development and differentiation, however, its role in T cell exhaustion was unexplored. Here, we aim to investigate the role of TOX in regulating the antitumor effect of CD8+ T cells in hepatocellular carcinoma.
Fully functional, partially and severely exhausted tumor-infiltrating CD8+ T cells were sorted by flow cytometry and subjected to transcriptome sequencing analysis. Upregulated TOX expression was validated by flow cytometry. The antitumor function of CD8+ T cells with TOX downregulation or overexpression was studied in a mouse HCC model and HCC patient-derived xenograft mouse model. Transcriptome sequencing analysis was performed in TOX-overexpressing and control CD8+ T cells. The mechanism underlying the TOX-mediated regulation of PD1 expression was studied by laser confocal detection, immune co-precipitation and flow cytometer.
TOX was upregulated in exhausted CD8+ T cells in hepatocellular carcinoma. TOX downregulation in CD8+ T cells inhibited tumor growth, increased CD8+ T cell infiltration, alleviated CD8+ T cell exhaustion and improved the anti-PD1 response of CD8+ T cells. The mechanism behind this involved the binding of TOX to PD1 in the cytoplasm, which facilitated the endocytic recycling of PD1, thus maintaining abundant PD1 expression at the cell surface. High expression of TOX in peripheral CD8+ T cells correlated with poorer anti-PD1 responses and prognosis.
TOX promotes CD8+ T cell exhaustion in hepatocellular carcinoma by regulating endocytic recycling of PD1. Downregulating TOX expression in CD8+ T cells exerts synergistic effects with anti-PD1 therapy, highlighting a promising strategy for cancer immunotherapy.
Abundant TOX expression in CD8+ T cells impairs their antitumor function in hepatocellular carcinoma. Mechanically, TOX reduces PD1 degradation and promotes PD1 translocation to the cell surface in CD8+ T cells, thus maintaining high PD1 expression at the cell surface. Downregulating TOX expression improves the antitumor function of CD8+ T cells, which shows the synergetic role of anti-PD1 therapy, highlighting a promising strategy for enhancement of cancer immunotherapy.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Author names in bold designate shared co-first authorship
- T cell dysfunction in cancer.Cancer Cell. 2018; 33: 547-562
- T cell exhaustion.Nat Immunol. 2011; 12: 492-499
- Molecular and cellular insights into T cell exhaustion.Nat Rev Immunol. 2015; 15: 486-499
- CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions.Annu Rev Med. 2018; 69: 301-318
- Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.Nat Rev Clin Oncol. 2018; 15: 325-340
- Cancer immunotherapy using checkpoint blockade.Science. 2018; 359: 1350-1355
- Fundamental mechanisms of immune checkpoint blockade therapy.Cancer Discovery. 2018; 8: 1069-1086
- Features of responding T cells in cancer and chronic infection.Curr Opin Immunol. 2010; 22: 223-230
- A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells.Cell. 2016; 166 (1500–1511 e1509)
- PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion.Immunity. 2016; 44: 1190-1203
- Development of all CD4 T lineages requires nuclear factor TOX.J Exp Med. 2008; 205: 245-256
- TOX provides a link between calcineurin activation and CD8 lineage commitment.J Exp Med. 2004; 199: 1089-1099
- TOX regulates growth, DNA repair, and genomic instability in T-cell acute lymphoblastic leukemia.Cancer Discovery. 2017; 7: 1336-1353
- The many roles of TOX in the immune system.Curr Opin Immunol. 2012; 24: 173-177
- 14-3-3zeta delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes.Cell Death Dis. 2018; 9: 159
- Defining T cell states associated with response to checkpoint immunotherapy in melanoma.Cell. 2018; 175 (998–1013 e1020)
- Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy.Immunity. 2019; 50 (195–211 e110)
- Regulatory circuits of T cell function in cancer.Nat Rev Immunol. 2016; 16: 599-611
- Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8(+) T cells.Immunity. 2018; 48 (773–786 e775)
- Interleukin-35 limits anti-tumor immunity.Immunity. 2016; 44: 316-329
- The diverse functions of the PD1 inhibitory pathway.Nat Rev Immunol. 2018; 18: 153-167
- PD-1 and its ligands in tolerance and immunity.Annu Rev Immunol. 2008; 26: 677-704
- Transcription factor IRF4 promotes CD8(+) T cell exhaustion and limits the development of memory-like T cells during chronic infection.Immunity. 2017; 47 (1129–1141 e1125)
- T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion.Nat Immunol. 2013; 14: 603-610
- Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.Science. 2016; 354: 1160-1165
- The epigenetic landscape of T cell exhaustion.Science. 2016; 354: 1165-1169
- FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.Nature. 2018; 564: 130-135
- CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity.Nature. 2017; 549: 101-105
- USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma.Cancer Lett. 2018; 433: 186-198
- TOX: an HMG box protein implicated in the regulation of thymocyte selection.Nat Immunol. 2002; 3: 272-280
- Association between expression level of PD1 by tumor-infiltrating CD8(+) T cells and features of hepatocellular carcinoma.Gastroenterology. 2018;
- The promise and challenges of immune agonist antibody development in cancer.Nat Rev Drug Discovery. 2018; 17: 509-527
- Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features.Gastroenterology. 2017; 153: 812-826
- Association between expression level of PD1 by tumor-infiltrating CD8(+) T cells and features of hepatocellular carcinoma.Gastroenterology. 2018; 155e1917
- IAP antagonists induce anti-tumor immunity in multiple myeloma.Nat Med. 2016; 22: 1411-1420
Published online: June 04, 2019
Accepted: May 22, 2019
Received in revised form: May 21, 2019
Received: December 28, 2018
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.