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

• Published in: Journal for immunotherapy of cancer 2019-11, Vol.7 (1), p.331-15, Article 331
• Main Authors: Ma, Jiaqiang, Zheng, Bohao, Goswami, Shyamal, Meng, Lu, Zhang, Dandan, Cao, Chunmei, Li, Teng, Zhu, Fangming, Ma, Lijie, Zhang, Zhao, Zhang, Shuhao, Duan, Meng, Chen, Qin, Gao, Qiang, Zhang, Xiaoming
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Cancer; Cancer therapies; Carcinoma; CD8; CD8+ T cells; Clinical outcomes; Cytotoxicity; DNA binding proteins; Flow cytometry; Hepatitis; Hepatocellular carcinoma; Immunohistochemistry; Immunotherapy; Immunotherapy Biomarkers; Liver; Liver cancer; Lymphocytes; Macrophages; Multiplex immunohistochemistry; Nivolumab; Patient outcomes; Pembrolizumab; Prognosis; Quantitative analysis; Regression analysis; Research Article; Response rates; Software; Spatial analysis; Statistical analysis; Surgery; T cell exhaustion; T cells; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-019-0814-7

BackgroundCD8+ 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.MethodsWe 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.ResultsCD8+ 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.ConclusionThe 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.