The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis

M J M Gooden, G H de Bock, N Leffers, T Daemen, H W Nijman, M J M Gooden, G H de Bock, N Leffers, T Daemen, H W Nijman

Abstract

Background: Tumour-infiltrating lymphocytes (TILs) are often found in tumours, presumably reflecting an immune response against the tumour. We carried out a systematic review and meta-analysis, aiming to establish pooled estimates for survival outcomes based on the presence of TILs in cancer.

Methods: A Pubmed and Embase literature search was designed. Studies were included, in which the prognostic significance of intratumoural CD3+, CD4+, CD8+, and FoxP3+ lymphocytes, as well as ratios between these subsets, were determined in solid tumours.

Results: In pooled analysis, CD3+ TILs had a positive effect on survival with a hazard ratio (HR) of 0.58 (95% confidence interval (CI) 0.43-0.78) for death, as did CD8+ TILs with a HR of 0.71 (95% CI 0.62-0.82). FoxP3+ regulatory TILs were not linked to overall survival, with a HR of 1.19 (95% CI 0.84-1.67). The CD8/FoxP3 ratio produced a more impressive HR (risk of death: HR 0.48, 95% CI 0.34-0.68), but was used in relatively few studies. Sample size and follow-up time seemed to influence study outcomes.

Conclusion: Any future studies should be carefully designed, to prevent overestimating the effect of TILs on prognosis. In this context, ratios between TIL subsets may be more informative.

Figures

Figure 1
Figure 1
Flowchart of study selection process.
Figure 2
Figure 2
Forest plots of studies on CD3+ TILs. Hazard ratios and 95% confidence intervals from individual studies are depicted as squares and horizontal lines, respectively. The pooled estimate is shown as a diamond shape, where the center represents the pooled HR and the horizontal borders represent the 95% CI. Hazard ratios are defined as high CD3 vs low CD3 counts, therefore a hazard ratio <1 represents a lower risk of death or progression associated with high CD3 counts.
Figure 3
Figure 3
Forest plots of studies on CD8+ TILs. Hazard ratios and 95% confidence intervals for death or progression associated with high vs low CD8 counts.
Figure 4
Figure 4
Forest plots of studies on FoxP3+ TILs. Hazard ratios and 95% confidence intervals for death or progression associated with high vs low FoxP3 counts.
Figure 5
Figure 5
Funnel plots. Funnel plots showing the associations between hazard ratios and s.e. for individual studies. (A) CD3+ TILs. (B) CD8+ TILs. (C) FoxP3+ TILs.

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