3.3 Synthesis of results and subgroup analysis for association
of high/low PD-L1 expression with prognostic factors
Meta-analysis of studies for OS indcated that PD-L1expression on TCs had
no significant effect on OS (HR, 1.10; 95% CI: [0.86, 1.40]; P
=0.461), and statistical heterogeneity (I2 = 80.7%, p
< 0.001) emerged(Supplemental Fig.S11) . Also for DSS
(Supplemental Fig.S12) , fifteen studies reported ready-made HR
or provided sufficient data to calculate the estimated HR that was
synthesised that yield a no statistically significant result (HR, 1.22;
95% CI: [0.86, 1.74]; P =0.258) with significant heterogeneity
(I2 = 62.6%, p < 0.001). Likewise, the
meta-analysis of studies for disease-free survival (DFS),
progression-free survival (PFS) and local-regional progression-free
survival (LRFS) were respectively performed, of which pooled estimated
HR were achieved correspondingly. Only the result for LRFS showed
significant finding (HR, 1.77; 95% CI: [1.20, 2.62]; P =0.004)
without significant heterogeneity (I2 = 0.0%, p =
0.590) (Supplemental Fig.S13) . Five studies assessed
association between the expression of PD-L1 on TILs and OS, of which the
pooled result showed no statistical significance (Supplemental
File 2 ). The estimated HR for DSS, DFS, PFS and LRFS were unattainable
to synthesize due to only one study reporting prognostic values.
Sources of heterogeneity might be attributed in part to geographic
region, scoring systems, antibody type, tumour anatomic location. Due to
the a lack of study on the relationship between PD-L1 expression on TILS
and prognosis, subgroup analysis was performed only on studies with
prognosis associated with TCs.
Geographic region was stratified for Asia and non-Asia with comparison
for prognostic value and showed no significant differences for OS, DSS.
Nevertheless, DFS showed high expression of PD-L1 in TCs was more likely
to have worse prognosis (HR, 1.65; 95% CI: [1.09, 2.49]; P =0.018)
(Supplemental Fig.S14) . Various scoring systems including
semiquantitative evaluation (SE), percentage of positive cell (PPC), CPS
, TPS, H score (combination of the staining distribution and intensity
scoring systems), were used to recombine these studies for OS, DSS and
DFS. There were no statistically significant results of prognosis showed
in TPS or CPS. Both DSS (HR, 1.65; 95% CI: [1.04, 2.64]; P =0.035)
and DFS (HR, 1.50; 95% CI: [1.15, 1.96]; P =0.003), at a 5%
cut-off of PPC, had positive association with high PD-L1
expression(Supplemental Fig.S15) .
Subgroup analysis decided by antibody type was carried out for OS, DSS
and DFS when two or more studies providing prognostic values for one
type of antibody. The results of OS showed that a worse prognosis for
5H1(HR, 2.50; 95% CI: [1.08, 5.76]; P =0.032), and a favourable
prognosis for 22C3(HR, 0.43; 95% CI: [0.27, 0.69]; P =0.001). For
DSS, high PD-L1 expression detecting by E1L3N was shown to be associated
with an worse prognosis(HR, 1.78; 95% CI: [1.13, 2.80]; P =0.014).
There was no evidence suggested the association of DFS with PD-L1
expression was determined by antibody type(Supplemental
Fig.S16) . Significant association of PD-L1 expressions in TCs with
staining location was not detected(Supplemental Fig.S17) . Seven
studies were viable for synthesising that reported OS in terms of
location of tongue. It was shown that high expressions of PD-L1 in TCs
had a worse prognosis in OSCC of the tongue (HR, 1.24; 95% CI: [1.03,
1.49]; P =0.023). Four studies assessed the DFS of PD-L1 expressions
and results showed that high PD-L1 expression in TCs was associated with
worse prognosis (HR, 2.03; 95% CI: [1.28, 3.22]; P
=0.003)(Fig.3 ). Only one study was available for PFS, LRFS that
was insufficient to combine.
Publication bias of studies in terms of the role of PD-L1 expressions in
clinicopathological and prognostic was determined by Egger’s tests and
was shown by funnel plots, of which results suggested absence of proof
(Supplemental File 3 ).