PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma

J Immunother Cancer. 2019 Nov 29;7(1):331. doi: 10.1186/s40425-019-0814-7.

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: PD1Hi, PD1Int and PD1-. PD1Hi CD8+ T cells were significantly enriched in tumor compared to adjacent non-tumor liver tissues. PD1Hi CD8+ T cells highly expressed exhaustion-related inhibitory receptors (TIM3, CTLA-4, etc.) and transcription factors (Eomes, BATF, etc.). In addition, PD1Hi 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, PD1Hi 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 PD1Hi or TIM3+PD1Hi 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 PD1Hi 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.

Keywords: CD8+ T cells; Hepatocellular carcinoma; Multiplex immunohistochemistry; Spatial analysis; T cell exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cytokines / metabolism
  • Gene Expression
  • Humans
  • Immunity
  • Immunohistochemistry
  • Immunophenotyping
  • Inflammation Mediators / metabolism
  • Kaplan-Meier Estimate
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Phenotype
  • Prognosis
  • Programmed Cell Death 1 Receptor / metabolism*
  • Tumor Microenvironment

Substances

  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor