Table 3

Tumoral immune cell infiltration in association with PD-L1 expression on tumor cells and prognosis

Reference	Immune cells	Method/cut-off	Correlation with PD-L1 expression	Prognosis
Konishi et al.⁴³	CD45, PD-1	%CD45+ and CD45+PD-1+TILs (per 1,000 nuclei or per 500 CD45+ cells) in PD-L1 positive and negative regions of 5 selected cases	Reduced CD45+ cells (22.6% vs. 51.5%, P=0.01) and reduced PD-1+CD45+ TILs (7.1% vs. 20.2%, P=0.02) in the PD-L1+ regions	N/A
Mu et al.⁴⁵	CD1a+ TIDC, CD83+ TIDC	Median value of all semiquantitative H-scores	Increased CD1a+ TIDC (no P-value described)	N/A
Velcheti et al.⁴⁶	TILs on HE	Semiquantitative scoring on a four-tiered scale*	Increased (grade 2-3) TILs in both Greece (P=0.0002) and US (P=0.001) cohorts	Increased TILs associated with longer OS in both Greece (log-rank P=0.015) and US (log-rank P=0.009) cohorts
Mao et al.⁴⁴	TIA-1, INF-γ	Positive TILs were counted in at least 5 HPFs within tumor cells and peritumoral stroma, and the final score was based on semiquantitative assessment on a four-tiered scale (0-1: low infiltration and 2-3: high infiltration)	NS	High infiltration of TIA-1+ and INF-γ+ TILs associated with longer OS (P<0.01 and P=0.02, respectively)
Boland et al.³⁶	TILs on HE	Semiquantitative scoring on a four-tiered scale	NS (average score 2.0 in PD-L1+ tumors and 1.9 in PD-L1 negative tumors)	N/A
Kim et al.⁴²	PD-1, CD8	The number of PD-1+ and CD8+ TILs per unit area were calculated from the intact tumor areas using Aperio, and the quantity of PD-1+ and CD8+ TILs in each case was classified as high and low using the median of all cases as a cut-off	Increased CD8+TILs (P<0.001), but not PD-1+ TILs	Increased PD-1+ TILs (>30/mm²) and CD8+ TILs (>450/mm²) associated with longer OS (P=0.042 and P=0.039, respectively)
Yang et al.⁴⁷	TILs on HE	Semiquantitative scoring on a four-tiered scale	NS	NS
Koh et al.¹⁹	PD-1, CD8	The number of PD-1+ and CD8+ TILs per unit area were calculated from the intact tumor areas using Aperio	The ratio of PD-1+/CD8+ TILs slightly higher in tumors with PD-L1 expression (P=0.066)	Increased PD-1+ TILs (>25/mm²) and CD8+ TILs (>100/mm²) associated with longer OS (P=0.025 and P=0.003, respectively) and high PD-1+ TILs/CD8+ TILs (>0.25) associated with shorter OS (P=0.030)
Lin et al.²⁰	PD-1, CD4, CD8	Semiquantitative H score was calculated for PD-1 expression in tumoral immune cells and the mean of all H scores was used as a cut-off. For CD4 and CD8, positive expression in TILs was semiquantitatively scored on a four-tiered scale, and score >1 was considered positive	NS	NS for PD-1, N/A for CD4 and CD8
Calles et al.³⁷	PD-1, CD3	Positive TILs were counted 5 (20x fields), and the average absolute number was recorded	Marginal association of higher number of PD-1+ TILs with strong intensity of PD-L1 expression in tumor cells, and PD-L1 expression >10% in immune cells associated to higher number of PD-1+ TILs (P=0.039)	N/A

N/A: not available; NS: not significant; TIDC: tumor infiltrating dendritic cells; TILs: tumor infiltrating lymphocytes.