PD1 CD8 T Cells Correlate with Exhausted Signature and Poor Clinical Outcome in Hepatocellular Carcinoma

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2019 Dec 1

PMID 31783783

Citations 162

Authors

Jiaqiang Ma

Bohao Zheng

Shyamal Goswami

Lu Meng

Dandan Zhang

Chunmei Cao

Teng Li

Fangming Zhu

Lijie Ma

Zhao Zhang

Shuhao Zhang

Meng Duan

Qin Chen

Qiang Gao

Xiaoming Zhang

Affiliations

Soon will be listed here.

Abstract

Background: CD8 T cells differentiate into exhausted status within tumors, including hepatocellular carcinoma (HCC), which constitutes a solid barrier to effective anti-tumor immunity. A detailed characterization of exhausted T cells and their prognostic value in HCC is lacking.

Methods: We collected fresh tumor tissues with adjacent non-tumor liver tissues and blood specimens of 56 HCC patients, as well as archived samples from two independent cohorts of HCC patients (n = 358 and n = 254), who underwent surgical resection. Flow cytometry and multiplex immunostaining were used to characterize CD8 T cells. Patient prognosis was evaluated by Kaplan-Meier analysis and Cox regression analysis.

Results: CD8 T cells were classified into three distinct subpopulations: PD1, PD1 and PD1. PD1 CD8 T cells were significantly enriched in tumor compared to adjacent non-tumor liver tissues. PD1 CD8 T cells highly expressed exhaustion-related inhibitory receptors (TIM3, CTLA-4, etc.) and transcription factors (Eomes, BATF, etc.). In addition, PD1 CD8 T cells expressed low levels of cytotoxic molecules and displayed a compromised capacity to produce pro-inflammatory cytokines while the expression of anti-inflammatory IL-10 was up-regulated following mitotic stimulation. Furthermore, PD1 CD8 T cells shared features with tissue resident memory T cells and were also characterized in an aberrantly activated status with an apoptosis-prone potential. In two independent cohorts of HCC patients (n = 358 and n = 254), we demonstrated that PD1 or TIM3PD1 CD8 T cells were significantly correlated with poor prognosis, and the latter was positioned in close proximity to PD-L1 tumor associated macrophages.

Conclusion: The current study unveils the unique features of PD1 CD8 exhausted T cells in HCC, and also suggests that exhausted T cells could act as a biomarker to select the most care-demanding patients for tailored therapies.

Citing Articles

Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer.

Zhang L, Guo X, Sun X, Liao J, Liu Q, Ye Y Front Immunol. 2025; 16:1486329.

PMID: 40040705 PMC: 11876966. DOI: 10.3389/fimmu.2025.1486329.

Molecular landscape of tumor-associated tissue-resident memory T cells in tumor microenvironment of hepatocellular carcinoma.

Park M, Jo H, Kim H, Kim J, Park W, Paik Y Cell Commun Signal. 2025; 23(1):80.

PMID: 39934824 PMC: 11818299. DOI: 10.1186/s12964-025-02070-w.

Liver sinusoidal endothelial cells regulate the balance between hepatic immunosuppression and immunosurveillance.

Kremer K, Khammash H, Miranda A, Rutt L, Twardy S, Anton P Front Immunol. 2025; 15:1497788.

PMID: 39896805 PMC: 11782242. DOI: 10.3389/fimmu.2024.1497788.

Prognostic significance of programmed cell death 1 expression on CD8+T cells in various cancers: a systematic review and meta-analysis.

Wan Z, Cui M, Yang J, Liao D, Chen J, Li F Front Oncol. 2025; 14:1531219.

PMID: 39876901 PMC: 11772205. DOI: 10.3389/fonc.2024.1531219.

Activin A promoted the anti-tumor effect of ActRIIA CD8 T cells in mouse hepatoma.

Hu L, Zhao Y, Zhang X, Ma C Cancer Med. 2024; 14(1):e70147.

PMID: 39727149 PMC: 11672029. DOI: 10.1002/cam4.70147.

References

Ganesan A, Clarke J, Wood O, Garrido-Martin E, Chee S, Mellows T . Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. 2017; 18(8):940-950. PMC: 6036910. DOI: 10.1038/ni.3775. View

Blackburn S, Shin H, Nicholas Haining W, Zou T, Workman C, Polley A . Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2008; 10(1):29-37. PMC: 2605166. DOI: 10.1038/ni.1679. View

Pacheco R, Martinez-Navio J, Lejeune M, Climent N, Oliva H, Gatell J . CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc Natl Acad Sci U S A. 2005; 102(27):9583-8. PMC: 1172240. DOI: 10.1073/pnas.0501050102. View

Ghoneim H, Fan Y, Moustaki A, Abdelsamed H, Dash P, Dogra P . De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017; 170(1):142-157.e19. PMC: 5568784. DOI: 10.1016/j.cell.2017.06.007. View

Blackburn S, Shin H, Freeman G, Wherry E . Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A. 2008; 105(39):15016-21. PMC: 2567485. DOI: 10.1073/pnas.0801497105. View

Gao Q, Wang X, Qiu S, Yamato I, Sho M, Nakajima Y . Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15(3):971-9. DOI: 10.1158/1078-0432.CCR-08-1608. View

Sade-Feldman M, Yizhak K, Bjorgaard S, Ray J, de Boer C, Jenkins R . Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018; 175(4):998-1013.e20. PMC: 6641984. DOI: 10.1016/j.cell.2018.10.038. View

Savas P, Virassamy B, Ye C, Salim A, Mintoff C, Caramia F . Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018; 24(7):986-993. DOI: 10.1038/s41591-018-0078-7. View

El-Khoueiry A, Sangro B, Yau T, Crocenzi T, Kudo M, Hsu C . Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017; 389(10088):2492-2502. PMC: 7539326. DOI: 10.1016/S0140-6736(17)31046-2. View

10.

Miller B, Sen D, Al Abosy R, Bi K, Virkud Y, LaFleur M . Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3):326-336. PMC: 6673650. DOI: 10.1038/s41590-019-0312-6. View

11.

Roncagalli R, Hauri S, Fiore F, Liang Y, Chen Z, Sansoni A . Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub. Nat Immunol. 2014; 15(4):384-392. PMC: 4037560. DOI: 10.1038/ni.2843. View

12.

Granier C, Dariane C, Combe P, Verkarre V, Urien S, Badoual C . Tim-3 Expression on Tumor-Infiltrating PD-1CD8 T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma. Cancer Res. 2016; 77(5):1075-1082. DOI: 10.1158/0008-5472.CAN-16-0274. View

13.

Wang C, Singer M, Anderson A . Molecular Dissection of CD8 T-Cell Dysfunction. Trends Immunol. 2017; 38(8):567-576. PMC: 5759349. DOI: 10.1016/j.it.2017.05.008. View

14.

Thommen D, Schreiner J, Muller P, Herzig P, Roller A, Belousov A . Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors. Cancer Immunol Res. 2015; 3(12):1344-55. DOI: 10.1158/2326-6066.CIR-15-0097. View

15.

Wu K, Kryczek I, Chen L, Zou W, Welling T . Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009; 69(20):8067-75. PMC: 4397483. DOI: 10.1158/0008-5472.CAN-09-0901. View

16.

Liu C, Xu J, Zhou Z, Jin L, Yu X, Xiao G . Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma. Br J Cancer. 2018; 119(1):80-88. PMC: 6035200. DOI: 10.1038/s41416-018-0144-4. View

17.

Mueller S, Mackay L . Tissue-resident memory T cells: local specialists in immune defence. Nat Rev Immunol. 2015; 16(2):79-89. DOI: 10.1038/nri.2015.3. View

18.

Li H, van der Leun A, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi A . Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell. 2019; 176(4):775-789.e18. PMC: 7253294. DOI: 10.1016/j.cell.2018.11.043. View

19.

Akimova T, Beier U, Wang L, Levine M, Hancock W . Helios expression is a marker of T cell activation and proliferation. PLoS One. 2011; 6(8):e24226. PMC: 3168881. DOI: 10.1371/journal.pone.0024226. View

20.

Gao Q, Qiu S, Fan J, Zhou J, Wang X, Xiao Y . Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007; 25(18):2586-93. DOI: 10.1200/JCO.2006.09.4565. View