Table 2.
Univariate and multivariate analysis for OS and DFS according to densities and Gcross functions of TILs subpopulations.
| Variables | Median IQR (cells/mm2) | Disease-free survival | Overall survival | ||
|---|---|---|---|---|---|
| Univariate HR (95% CI) | Multivariate HR (95% CI) a | Univariate HR (95% CI) | Multivariate HR (95% CI) a | ||
| Density | |||||
| TILs | 2260.1 (1721.2-3213.1) | ||||
| High vs Low | 1.13 (0.66-1.94) | 1.27 (0.73-2.22) | 1.12 (0.56-2.22) | 1.19 (0.58-2.42) | |
| p value | 0.647 | 0.402 | 0.747 | 0.636 | |
| CTLs | 582.1 (242.7-1225.1) | ||||
| High vs Low | 0.84 (0.49-1.44) | 0.75 (0.42-1.32) | 0.77 (0.38-1.53) | 0.69 (0.34-1.42) | |
| p value | 0.539 | 0.317 | 0.45 | 0.316 | |
| Teffs | 140.1 (69.8-318.6) | ||||
| High vs Low | 1.64 (0.94-2.84) | 1.83 (1.03-3.23) | 1.47 (0.73-2.95) | 1.38 (0.67-2.82) | |
| p value | 0.078 | 0.039 | 0.279 | 0.382 | |
| Tregs | 58.2 (19.0-142.0) | ||||
| High vs Low | 1.79 (1.03-3.12) | 1.94 (1.09-3.42) | 1.71 (0.85-3.46) | 1.71 (-.83-3.51) | |
| p value | 0.040 | 0.023 | 0.136 | 0.146 | |
| PDL1+TILs | 1037.4 (711.5-1709.1) | ||||
| High vs Low | 0.90 (0.53-1.55) | 0.934 (0.54-1.62) | 1.01 (0.54-2.13) | 1.23 (0.61-2.46) | |
| p value | 0.701 | 0.807 | 0.836 | 0.563 | |
| PDL1+TCs | 3113.8 (1043.4-5461.6) | ||||
| High vs Low | 0.78 (0.46-1.34) | 0.76 (0.42-1.35) | 1.39 (0.70-2.77) | 0.72 (0.35-1.47) | |
| p value | 0.371 | 0.351 | 0.342 | 0.369 | |
| PDL1+CTLs | 223.7 (76.0-466.6) | ||||
| High vs Low | 0.74 (0.43-1.27) | 0.68 (0.38-1.20) | 0.54 (0.26-1.09) | 0.55 (0.26-1.13) | |
| p value | 0.274 | 0.180 | 0.085 | 0.105 | |
| PDL1+Teffs | 69.7 (33.5-148.3) | ||||
| High vs Low | 1.87 (1.07-3.27) | 2.07 (1.18-3.65) | 1.27 (0.64-2.52) | 1.40 (0.69-2.83) | |
| p value | 0.027 | 0.012 | 0.497 | 0.348 | |
| PDL1+Tregs | 32.2 (11.5-63.7) | ||||
| High vs Low | 2.34 (1.32-4.14) | 2.54 (1.42-4.56) | 2.00 (0.98-4.08) | 2.01 (0.98-4.15) | |
| p value | 0.003 | 0.002 | 0.055 | 0.058 | |
| Gcross function value b | |||||
| GTC : Treg | 1.80 (0.55-4.35) | ||||
| High vs Low | 2.35 (1.33-4.15) | 2.43 (1.34-4.42) | 2.27 (1.10-4.69) | 2.20 (1.04-4.63) | |
| p value | 0.003 | 0.004 | 0.026 | 0.039 | |
| GTC : PDL1+Treg | 1.07 (0.40-2.61) | ||||
| High vs Low | 1.61(0.93-2.79) | 1.68 (0.96-2.95) | 1.62 (0.81-3.26) | 1.57 (0.77-3.18) | |
| p value | 0.090 | 0.072 | 0.176 | 0.215 | |
| GCTL : Treg | 9.19 (3.49-17.12) | ||||
| High vs Low | 2.01 (1.14-3.52) | 2.16 (1.21-3.87) | 1.96 (0.96-4.00) | 1.78 (0.86-3.68) | |
| p value | 0.015 | 0.009 | 0.066 | 0.121 | |
| GCTL : PDL1+Treg | 4.21 (1.38-9.41) | ||||
| High vs Low | 2.08 (1.18-3.65) | 2.15 (1.21-3.80) | 2.03 (0.99-4.15) | 2.08 (1.00-4.29) | |
| p value | 0.011 | 0.009 | 0.053 | 0.049 | |
| 20 um radius | |||||
| GTC : Treg | 0.0008 (0.0002-0.0031) | ||||
| High vs Low | 1.67 (0.96-2.89) | 1.75 (0.98-3.12) | 1.42 (0.71-2.83) | 1.44 (0.70-2.95) | |
| p value | 0.069 | 0.060 | 0.32 | 0.326 | |
| GTC : PDL1+Treg | 0.0006 (0.0000-0.0017) | ||||
| High vs Low | 1.21 (0.71-2.07) | 1.23 (0.70-2.15) | 1.09 (0.55-2.15) | 1.04 (0.51-2.10) | |
| p value | 0.493 | 0.467 | 0.808 | 0.918 | |
| GCTL : Treg | 0.0089 (0.0014-0.0212) | ||||
| High vs Low | 2.29 (1.29-4.04) | 2.39 (1.33-4.29) | 2.31 (1.11-4.80) | 2.06 (0.99-4.30) | |
| p value | 0.004 | 0.003 | 0.025 | 0.053 | |
| GCTL : PDL1+Treg | 0.0034 (0.000-0.0104) | ||||
| High vs Low | 2.01 (1.15-3.53) | 2.14 (1.21-3.80) | 1.70 (0.84-3.44) | 1.79 (0.88-3.64) | |
| p value | 0.011 | 0.009 | 0.139 | 0.110 | |
| 30 um radius | |||||
| GTC : Treg | 0.0037 (0.001-0.0111) | ||||
| High vs Low | 2.17 (1.24-3.81) | 2.25 (1.24-4.09) | 1.98 (0.98-4.04) | 2.01 (0.97-4.19) | |
| p value | 0.007 | 0.008 | 0.058 | 0.062 | |
| GTC : PDL1+Treg | 0.0026 (0.0006-0.0067) | ||||
| High vs Low | 1.64 (0.94-2.84) | 1.72 (0.97-3.04) | 1.63 (0.81-3.28) | 1.62 (0.79-3.22) | |
| p value | 0.080 | 0.065 | 0.170 | 0.183 | |
| GCTL : Treg | 0.0326 (0.0088-0.0670) | ||||
| High vs Low | 2.26 (1.28-3.40) | 2.37 (1.31-4.30) | 2.29 (1.20-4.75) | 1.91 (0.91-4.01) | |
| p value | 0.005 | 0.004 | 0.027 | 0.087 | |
| GCTL : PDL1+Treg | 0.0161 (0.0028-0.0319) | ||||
| High vs Low | 2.20 (1.25-3.87) | 2.43 (1.37-4.30) | 2.14 (1.04-4.37) | 2.20 (1.07-4.54) | |
| p value | 0.006 | 0.002 | 0.038 | 0.032 | |
| 50 um radius | |||||
| GTC : Treg | 0.0127 (0.0036-0.0342) | ||||
| High vs Low | 2.42 (1.37-4.28) | 2.38 (1.32-4.30) | 2.33 (1.13-4.80) | 2.19 (1.05-4.58) | |
| p value | 0.002 | 0.004 | 0.022 | 0.037 | |
| GTC : PDL1+Treg | 0.0071 (0.0027-0.0201) | ||||
| High vs Low | 1.99 (1.12-3.49) | 2.00(1.12-3.56) | 2.19 (1.06-4.51) | 2.07 (0.99-4.32) | |
| p value | 0.017 | 0.019 | 0.034 | 0.054 | |
| GCTL : Treg | 0.0842 (0.0265-0.1597) | ||||
| High vs Low | 1.78 (1.02-3.10) | 1.91 (1.07-3.41) | 1.70 (0.84-3.44) | 1.56 (0.76-3.21) | |
| p value | 0.042 | 0.028 | 0.139 | 0.230 | |
| GCTL : PDL1+Treg | 0.0384 (0.0110-0.0855) | ||||
| High vs Low | 2.34 (1.32-4.14) | 2.45 (1.38-4.38) | 2.37 (1.14-4.91) | 2.35 (1.12-4.92) | |
| p value | 0.003 | 0.003 | 0.021 | 0.023 | |
a
,Cox proportional hazards regression model adjusted for age, sex, N stage, T stage, TNM stage, smoking history, histological type.
b
,Gcross function values measured as the probability of finding at least one Treg/PDL1+Tregs within a given radius from a tumor cell or CTLs.
CI, confidence interval; HR, hazard ratio; IQR, interquartile range.
TILs, tumor infiltrating lymphocytes; CTLs, cytotoxic T lymphocytes; Teffs, positive effector T cells; Tregs, regulatory T cells; PDL1+ TILs, PDL1 positive tumor infiltrating lymphocytes; PDL1+TCs, PDL1 positive tumor cells; PDL1+CTLs, PDL1 positive cytotoxic T lymphocytes; PDL1+Teffs, PDL1 positive effector T cells; PDL1+Tregs, PDL1 positive regulatory T cells.