PD-1/PD-L1 upregulation may be due to cytokine stimulations in the tumor microenvironment. Growing investigations demonstrate that PD-1 extensively upregulated on tumor Ag-specific T cells in cancer patients and play a crucial role in the mechanism of tumor evasion by inhibiting the proliferation, cytokine-secretion and cytoxicity of tumor Agspecific T cells. Especially, Our previous study show that the interaction between PD-1 and intratumoral PD-L1 promote the apoptosis of CD8+ T cells, which probably contribute to the low expression of tumor Ag-specific T cells in patients with hepatocellular carcinoma. There are two main pathways promoting PD-1 expression on CD8+T cells. One is by antigen specific stimulation; the other is by the cytokine pathway, through which PD-1 upregulations are promoted on non-tumor Ag-specific T cells. Here, we propose that the upregulation of PD-1 on nontumor Ag-specific T cells should constrain the tumor-associated inflammation to a much milder degree, which hereafter favor the tumor differentiation and proliferation. However, further investigations should be carried out to elucidate the detailed mechanism of this issue. In the present study, we also found patients with recurrent tumors, which would generally be smaller than primary ones, associated with higher PD-1/PD-L1 expression. According to former investigations, we believe that it is the tumor-associated inflammation, rather than tumor volume, which promote the elevated expression of PD-1 and PD-L1. After cryoablation therapy, tumor cells were degenerated, disaggregated and uptaken by antigen presenting cells, e.g. kuffer cells, pDC and mDC, which lead to the secretion of a large mount of Y-27632 dihydrochloride proinflammatory cytokines, including IFN-a,IFN-c and gamma-chain cytokines. In detail, interferons could promote PD-L1 expression on both tumor cells and antigen presenting cells in comparison with that gammachain cytokines account for PD-1 elevations on CD8+T cells. Thus, both PD-1 and PD-L1 expression was significantly upregulate at the first week post-cryoablation. Together with the resolution of tumor burden, the immune system goes in to a quiescent phase, manifesting lower PD-1 and PD-L1 expression. When recurrence occurs, the immune system should be re-activated and promote an inflammation, both of which favor PD-1 and PD-L1 re-elevation, in comparison with the expression at week 4 post cryoablation therapy, at the time when patients are free of tumor burden. Tumor diameter,portal vein tumor thrombus, microvessel invasion, and tumor capsule invasion are the main high risk factors.