Table 2.

Univariate and multivariate survival analyses for immune-checkpoint expression in DLBCL evaluated by cell density and tissue cellularity

Univariate analysisMultivariate analysis for OSMultivariate analysis for PFS
Cutoff; prevalenceImpact in overall DLBCLImpact in T-cell–infiltrated DLBCLHR (95% CI)PHR (95% CI)P
Cell density of expression-positive cells
High PD-1+CD8+ T-cell density≥671 cells/mm2; 21%Poorer PFS: P = 0.0096 (P = 0.066 for poorer OS)Poorer OS: P = 0.014; poorer PFS: P = 0.0018 in CD8+ patients1.80 (1.14–2.85)0.0112.00 (1.31–3.05)0.001
High PD-L1+ T-cell density≥248 cells/mm2; 20.2%Poorer OS: P = 0.031 (P = 0.064 for poorer PFS)Poorer OS: P = 0.0075; poorer PFS: P = 0.02 in CD3+ patients1.93 (1.23–3.03)0.0041.84 (1.20–2.83)0.006
High PD-L1+ Th cell density≥123 cells/mm2; 24.9%Poorer OS: P = 0.019; poorer PFS: P = 0.043Poorer OS: P = 0.0028; poorer PFS: P = 0.0097 in CD4+ patients1.68 (1.10–2.58)0.0171.59 (1.06–2.38)0.025
High PD-L1+CD68+ cell density≥769 cells/mm2; 9.9%Poorer OS: 0.04 (P = 0.085 for PFS)Poorer OS: 0.0092; poorer PFS: 0.023 in CD3+ patients1.50 (0.86–2.63)0.15 in CD3+ patients1.43 (0.84–2.46)0.19 in CD3+ patients
High PD-L1+CD20+ B-cell density≥1,467 cells/mm2; 13%Better PFS: P = 0.023 (P = 0.055 for better OS)Better PFS: P = 0.047 (P = 0.093 for OS) in CD3+ patients0.50 (0.27–0.95)0.0340.51 (0.28–0.92)0.024
High PD-L2+CD20+ B-cell density≥1,877 cells/mm2; 3.7%Better OS: P = 0.0084; better PFS: P = 0.012Better OS: P = 0.01; better PFS: P = 0.0048 in CD3+ patients0.970.96
Tissue cellularity of expression-positive cells
High tissue cellularity of PD-1+CD8+ T cells>2.2% of DAPI+ cells; 43.5%Poorer PFS: P = 0.014 (P = 0.13 for OS)Poorer OS: P = 0.01; poorer PFS: P = 0.0008 in CD8+ patients1.66 (1.08–2.56)0.021.73 (1.16–2.58)0.007
High tissue cellularity of PD-1+CD4+ T cells>1.4% of DAPI+ cells; 60%Poorer PFS: P = 0.043 (P = 0.22 for OS)Poorer OS: P = 0.01; poorer PFS: P = 0.0012 in CD4+ patients1.56 (0.98–2.48)0.0591.55 (1.01–2.38)0.046
High tissue cellularity of PD-L1+ T cells≥2.0% of DAPI+ cells; 24%Marginal P for poorer OS: P = 0.058 (P = 0.16 for PFS)Poorer OS: P = 0.014; poorer PFS: P = 0.053 in CD3+ patients1.71 (1.12–2.61)0.0121.65 (1.10–2.46)0.014
High tissue cellularity of PD-L1+CD68+ cells≥6.0% of DAPI+ cells; 13.3%Poorer OS: P = 0.039; poorer PFS: P = 0.01Poorer OS: P = 0.012; poorer PFS: P = 0.0035 in CD3+ patients1.36 (0.84–2.22)0.21 in CD3+ patients1.6 (1.03–2.57)Not significant in DLBCL. 0.038 in CD3+ patients
Positive tissue cellularity of PD-1+CD20+ B cells≥0.22% of DAPI+ cells; 17.6%Better OS: P = 0.05 (P = 0.084 for PFS)Not significant (P = 0.082 for OS and P = 0.17 for PFS) in CD3+ patients0.58 (0.32–1.03)0.0610.71 (0.43–1.19)0.19
High tissue cellularity of PD-L1+CD56+ cells≥1.1% of DAPI+ cells; 4.4%Better OS: 0.013; better PFS: 0.02Better OS: P = 0.027; better PFS: P = 0.027 in CD3+ patients0.14 (0.019–0.99)0.0490.25 (0.061–1.01)0.051
High tissue cellularity of PD-L1+CD20+ B cells≥16.6% of DAPI+ cells; 8.6%Better OS: P = 0.05 (P = 0.075 for better PFS)Not significant (P = 0.071 for better OS and P = 0.12 for PFS) in CD3+ patients0.39 (0.18–0.84)0.0170.52 (0.27–0.99)0.048
High tissue cellularity of PD-L2+CD20+ B cells>13% of DAPI+ cells; 4.9%Better OS: P = 0.0082; better PFS: P = 0.0086Better OS: P = 0.015; better PFS: P = 0.0078 in CD3+ patients0.12 (0.017–0.90)0.0390.10 (0.014–0.75)0.025
High tissue cellularity of CTLA-4+CD3+ cells≥0.79% of DAPI+ cells; 18.5%Better OS: P = 0.007 (P = 0.08 for better PFS)Better OS: P = 0.017 (PFS: P = 0.16) in CD3+ patients0.53 (0.29–0.98)0.0440.79 (0.48–1.30)0.35
  • NOTE: For multivariate survival analyses, Cox models were used and the factors included high International Prognostic Index score, sex, B-symptoms, >5-cm tumor size, and individual immune-checkpoint expression. For PD-1/PD-L1 expression in T cells, analyses were performed in patients with T-cell infiltration. For expression in other cell types (except for PD-L1+CD68+ cell cellularity as indicated), analyses were performed in the overall DLBCL cohort.

  • Significant P values are in bold.

  • Abbreviations: HR, hazard ratio; CI, confidence interval; Th, helper T cells, CD3+CD4+FOXP3 cells.