Highlights
- •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.
Methods
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.
Results
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.
Conclusions
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.
Lay summary
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 04, 2019
Accepted:
May 22,
2019
Received in revised form:
May 21,
2019
Received:
December 28,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
