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

J Ma, B Zheng, S Goswami, L Meng, D Zhang… - … for immunotherapy of …, 2019 - Springer
J Ma, B Zheng, S Goswami, L Meng, D Zhang, C Cao, T Li, F Zhu, L Ma, Z Zhang, S Zhang…
Journal for immunotherapy of cancer, 2019Springer
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 …
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.
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