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. 2019 Dec;68(12):2041-2054.
doi: 10.1007/s00262-019-02426-5. Epub 2019 Nov 12.

PD-1+ TIGIT+ CD8+ T cells are associated with pathogenesis and progression of patients with hepatitis B virus-related hepatocellular carcinoma

Xiaoli Liu  1 , Mengge Li  2 , Xinhui Wang  1 , Zhibo Dang  1 , Yuyong Jiang  1 , Xianbo Wang  1 , Yaxian Kong  3 , Zhiyun Yang  4
Affiliations

PD-1+ TIGIT+ CD8+ T cells are associated with pathogenesis and progression of patients with hepatitis B virus-related hepatocellular carcinoma

Xiaoli Liu et al. Cancer Immunol Immunother. 2019 Dec.

Abstract

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4+ and CD8+ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1+ TIGIT+ CD8+ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1+ TIGIT+ CD8+ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1+ TIGIT+ CD8+ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1+ TIGIT+ CD8+ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy.

Keywords: Coexpression; HCC; Prognosis; Programmed cell death-1; TIGIT.

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Conflict of interest statement

The authors declare that they have no conflict of interests.

Figures

Fig. 1
Fig. 1
Coexpression of PD-1 and TIGIT is upregulated on T cells in HBV-HCC patients. a, b The expression of PD-1 and TIGIT on CD4+ and CD8+ T cells from HBV-HCC (n = 122), compared with healthy donors (n = 35), CHB (n = 20) LC patients (n = 27) by flow cytometry analysis. c Correlation analysis of PD-1 and TIGIT on CD4+ T cells (left) and CD8+ T cells (right) from patients with HBV-HCC. d Representative flow data of PD-1 and TIGIT expression on CD4+ and CD8+ T cells within each group. e Percentages of PD-1+ TIGIT+ CD4+ cells (left) and PD-1+ TIGIT+ CD8+ cells (right) of all CD4 and CD8 T cells, respectively, from patients with HBV-HCC. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Fig. 2
Fig. 2
Kaplan–Meier curve analysis showing the efficacy of PD-1+ TIGIT+ CD8+ cell levels as a predictor of progression-free survival in HBV-HCC across different tumor burdens. a, b Kaplan–Meier curve analysis showing the efficacy of PD-1+ TIGIT+ CD8+ cell levels as a predictor of overall survival (a) and progression-free survival (b) in HBV-HCC patients. (c) ROC curve for PD-1+ TIGIT+ CD8+ T cell, PD-1+ CD8+ T cell and TIGIT+ CD8+ T-cell frequency as a predictor of progression-free survival for HBV-HCC patients. d–i Subgroup analysis of patients with (d) BCLC stage A and B HCC, (e) BCLC stage C and D HCC, (f) patients with tumor size < 5 cm, (g) patients with tumor size > 5 cm, (h) patients with single tumors, and (i) patients with multiple tumors. P values and HRs were obtained using the log-rank test
Fig. 3
Fig. 3
Kaplan–Meier curve analysis showing the efficacy of PD-1+ TIGIT+ CD8+ cell levels as a predictor of progression-free survival in HBV-HCC across different liver function scores, HBV virus load, and AFP levels and treatments. a, b Patients with different MELD scores, c, d patients with different levels of serum HBV-DNA, (e) patients with or without antiviral therapy, (f–h) patients with different levels of serum AFP, (i) patients with resection, minimally invasive treatment or palliative treatment. P values and HRs were obtained using the log-rank test
Fig. 4
Fig. 4
PD-1+ TIGIT+ CD8+ cells in HBV-HCC patients exhibit an exhausted phenotype and overactivation. a–b Distribution of TN, TCM, TEM, and TEMRA cells in CD8+ T-cell populations derived from patients with CHB, LC, and HCC. Representative flow cytometry data gated on CD8 (a) and histograms showing the percentage of each T-cell subset in each group (b) are shown (n = 20, 27, and 48 for the CHB, LC, and HCC groups, respectively). c Percentages of PD-1+ TIGIT+ on each subset (TN, TCM, TEM, and TEMRA) of CD8+ T cells. d–e Representative flow cytometry data (d) and plots (e) showing the percentage of HLA-DR+, CD38+, and CD38+ HLA-DR+ subpopulations within PD-1− TIGIT−, PD-1+ TIGIT−, PD-1− TIGIT+, and PD-1+ TIGIT+ CD8+ T-cell populations from patients with HBV-HCC (n = 20). f Frequency of 2B4, LAG-3, CTLA-4 and TIM-3 on PD-1− TIGIT−, PD-1+ TIGIT−, PD-1− TIGIT+, and PD-1+ TIGIT+ CD8+ T cells from HBV-HCC patients. **P < 0.01, ***P < 0.001, ****P < 0.0001
Fig. 5
Fig. 5
PD-1+ TIGIT+ CD8+ T cells are defective in cytokine production, susceptible to apoptosis, and display unique patterns of T-bet/Eomes expression. a, b Intracellular staining for IFN-γ (a) and TNF-α (b) in PD-1+ TIGIT+ CD8+ T cells from HBV-HCC patients (n = 19) upon in vitro anti-CD3/anti-CD28 stimulation. c–d Percentage of apoptotic (Annexin V+ 7AAD−) cells and expression of CD95 on PD-1− TIGIT−, PD-1+ TIGIT−, PD-1− TIGIT+ and PD-1+ TIGIT+ CD8+ T cells from patients with HBV-HCC (n = 13). e–f Representative flow cytometry data (e) and histogram (f) showing the percentage of T-betdim/Eomeshi and T-bethi/Eomesdim cells in different subpopulations of PD-1+ TIGIT+ CD8+ T cells from patients with HBV-HCC (n = 20). *P < 0.05, **P < 0.01, ***P < 0.001
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