TGF-β-p-STAT1-LAIR2 Axis Has a "self-rescue" Role for Exhausted CD8 T Cells in Hepatocellular Carcinoma

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2023 May 24

PMID 37223874

Authors

Banglun Pan

Zengbin Wang

Yuxin Yao

Xiaoling Ke

Shuling Shen

Weihong Chen

Xiaoxia Zhang

Jiacheng Qiu

Xiaoxuan Wu

Nanhong Tang

Affiliations

Soon will be listed here.

Abstract

Background: TGF-β is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-β affecting the function of CD8 T cells in hepatocellular carcinoma (HCC) have not been clearly resolved.

Methods: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-β on HCC infiltrating CD8 T cells.

Results: Here, we demonstrated that the overall effect of TGF-β on CD8 T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-β upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-β-p-STAT1-LAIR2 axis relieved CD8 T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-β stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8 T cells was improved by using TAK-981 to amplify "self-rescue" signal.

Conclusion: Our study describes a "self-rescue" mechanism of CD8 T cells in HCC against exhaustion and the good effects from amplifying this signal.

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References

Zebley C, Gottschalk S, Youngblood B . Rewriting History: Epigenetic Reprogramming of CD8 T Cell Differentiation to Enhance Immunotherapy. Trends Immunol. 2020; 41(8):665-675. PMC: 7395868. DOI: 10.1016/j.it.2020.06.008. View

Zheng C, Zheng L, Yoo J, Guo H, Zhang Y, Guo X . Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell. 2017; 169(7):1342-1356.e16. DOI: 10.1016/j.cell.2017.05.035. View

Morita M, Nishida N, Sakai K, Aoki T, Chishina H, Takita M . Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody. Liver Cancer. 2021; 10(4):380-393. PMC: 8339510. DOI: 10.1159/000516899. View

Yang L, Pang Y, Moses H . TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010; 31(6):220-7. PMC: 2891151. DOI: 10.1016/j.it.2010.04.002. View

Kim Y, Stringfield T, Chen Y, Broxmeyer H . Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. Blood. 2004; 105(1):274-81. DOI: 10.1182/blood-2003-12-4343. View

Rodriguez-Ruiz M, Rodriguez I, Mayorga L, Labiano T, Barbes B, Etxeberria I . TGFβ Blockade Enhances Radiotherapy Abscopal Efficacy Effects in Combination with Anti-PD1 and Anti-CD137 Immunostimulatory Monoclonal Antibodies. Mol Cancer Ther. 2019; 18(3):621-631. DOI: 10.1158/1535-7163.MCT-18-0558. View

Guo Y, Wu H, Xiong J, Gou S, Cui J, Peng T . miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer. Cell Biol Toxicol. 2022; 39(4):1203-1214. DOI: 10.1007/s10565-022-09736-y. View

Mrdjen D, Pavlovic A, Hartmann F, Schreiner B, Utz S, Leung B . High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity. 2018; 48(2):380-395.e6. DOI: 10.1016/j.immuni.2018.01.011. View

Satija R, Farrell J, Gennert D, Schier A, Regev A . Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015; 33(5):495-502. PMC: 4430369. DOI: 10.1038/nbt.3192. View

10.

Wolock S, Lopez R, Klein A . Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Syst. 2019; 8(4):281-291.e9. PMC: 6625319. DOI: 10.1016/j.cels.2018.11.005. View

11.

Becht E, McInnes L, Healy J, Dutertre C, Kwok I, Ng L . Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol. 2018; . DOI: 10.1038/nbt.4314. View

12.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

13.

Hahne F, LeMeur N, Brinkman R, Ellis B, Haaland P, Sarkar D . flowCore: a Bioconductor package for high throughput flow cytometry. BMC Bioinformatics. 2009; 10:106. PMC: 2684747. DOI: 10.1186/1471-2105-10-106. View

14.

Finak G, Jiang W, Pardo J, Asare A, Gottardo R . QUAliFiER: an automated pipeline for quality assessment of gated flow cytometry data. BMC Bioinformatics. 2012; 13:252. PMC: 3499158. DOI: 10.1186/1471-2105-13-252. View

15.

Hartmann F, Bernard-Valnet R, Queriault C, Mrdjen D, Weber L, Galli E . High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J Exp Med. 2016; 213(12):2621-2633. PMC: 5110028. DOI: 10.1084/jem.20160897. View

16.

Trempolec N, Dave-Coll N, Nebreda A . SnapShot: p38 MAPK signaling. Cell. 2013; 152(3):656-656.e1. DOI: 10.1016/j.cell.2013.01.029. View

17.

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

18.

Chen D, Mellman I . Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541(7637):321-330. DOI: 10.1038/nature21349. View

19.

Li B, Chan H, Chen P . Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem. 2017; 26(17):3009-3025. DOI: 10.2174/0929867324666170804143706. View

20.

Lundgren S, Keranen M, Kankainen M, Huuhtanen J, Walldin G, Kerr C . Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia. Leukemia. 2021; 35(5):1365-1379. PMC: 8102188. DOI: 10.1038/s41375-021-01231-3. View