TY - JOUR T1 - PD1<sup>Hi</sup> CD8<sup>+</sup> T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-019-0814-7 VL - 7 IS - 1 SP - 331 AU - Jiaqiang Ma AU - Bohao Zheng AU - Shyamal Goswami AU - Lu Meng AU - Dandan Zhang AU - Chunmei Cao AU - Teng Li AU - Fangming Zhu AU - Lijie Ma AU - Zhao Zhang AU - Shuhao Zhang AU - Meng Duan AU - Qin Chen AU - Qiang Gao AU - Xiaoming Zhang Y1 - 2019/12/01 UR - http://jitc.bmj.com/content/7/1/331.abstract N2 - 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.Jiaqiang Ma, Bohao Zheng, Shyamal Goswami and Lu Meng contributed equally to this work.Abbreviations:CTLA4Cytotoxic T-lymphocyte antigen 4HCCHepatocellular carcinomaILInterleukinLAG3Lymphocyte activation gene 3OSOverall survivalPD-1Programmed cell death 1PD-L1Programmed cell death-ligand 1RFSRelapse free survivalTAMsTumor associated macrophagesTIGITT cell immunoreceptor with Ig and ITIM domainsTILsTumor-infiltrating lymphocytesTIM-3T cell immunoglobulin domain and mucin domain-3TMATissue microarrayTNMTumor-nodes-metastases ER -