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Review
. 2019 Jan;98(2):e13923.
doi: 10.1097/MD.0000000000013923.

Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma: A meta-analysis

Xuezhong Xu  1 , Yulin Tan  1 , Yan Qian  2 , Wenbo Xue  1 , Yibo Wang  1 , Jianguo Du  1 , Lei Jin  1 , Wei Ding  1
Affiliations
Review

Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma: A meta-analysis

Xuezhong Xu et al. Medicine (Baltimore). 2019 Jan.

Abstract

Background: In patients with hepatocellular carcinoma (HCC), the clinicopathologic and prognostic roles of tumor-infiltrating CD8+ T cells for survival are still controversial. A meta-analysis was performed to resolve this issue.

Methods: We identified studies from PubMed, Embase, and the Cochrane Library to evaluate the clinicopathologic and prognostic value of tumor-infiltrating CD8+ T cells in patients with HCC. A meta-analysis was conducted to estimate clinicopathologic characteristics, overall survival (OS), and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials.

Results: A total of 3509 patients from 21 observational studies were enrolled. The meta-analysis revealed that high levels of intratumoral CD8+ tumor-infiltrating lymphocytes (TILs) were associated with better OS (OS; HR = 0.676, P = .001) and disease-free survival (disease-free survival [DFS]; HR = 0.712, P = .002). The pooled analysis also demonstrated high density of infiltration of CD8+ TILs in margin of tumor (MT) was statistically significant associated with better OS (HR = 0.577; P <.001). Moreover, the patients with low CD8+ TILs infiltration had negative HBSAg (OR = 1.67, P = .02), large tumor size (OR = 1.74, P <.01), and later TNM stage (OR = 1.70, P <.01).

Conclusions: Our findings suggested that low levels of CD8+ TILs predict large tumor size, later TNM stage and might be a promising prognostic factor of HCC especially for Asian patients. High-quality randomized controlled trials are needed to determine if CD8+ TILs could serve as targets for immunotherapy in hepatocellular carcinoma.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flow diagram of study selection.
Figure 2
Figure 2
Forest plots of studies evaluating the association between CD8+ lymphocytes and OS of HCC patients. OS = overall survival, HCC = hepatocellular carcinoma.
Figure 3
Figure 3
Forest plots of studies evaluating the association between CD8+ lymphocytes and DFS of HCC patients. DFS = disease free survival, HCC = hepatocellular carcinoma.
Figure 4
Figure 4
Cumulative meta-analysis of the association between CD8+ TILs and prognosis. (A) Intratumoral CD8+ lymphocytes and OS; (B) Intratumoral CD8+ lymphocytes and DFS. DFS = disease free survival, OS = overall survival, TILs = tumor-infiltrating lymphocytes.
Figure 5
Figure 5
Sensitivity analyses of the association between CD8+ TILs and prognosis. (A) Sensitivity analysis of the association between CD8+ lymphocytes in IT and OS; (B) Sensitivity analysis of the association between CD8+ lymphocytes in IT and DFS. DFS = disease free survival, IT = intratumor, OS = overall survival, TILs = tumor-infiltrating lymphocytes.
Figure 6
Figure 6
Egger's tests of the association between CD8+ TILs and prognosis. (A) Egger's tests of the association between CD8+ lymphocytes in IT and OS; (B) Egger's tests of the association between CD8+ lymphocytes in IT and DFS. DFS = disease free survival, IT = intratumor, OS = overall survival, TILs = tumor-infiltrating lymphocytes.
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