Table 2.
Univariable and multivariable Cox regression models for disease-free survival according to M1- and M2-polarized macrophage density and Gcross spatial measurements between tumor cells and macrophages within 20μm radius.
| Myeloid immune cell subseta | No. of patients | Cell Density, Median (IQR) (1/mm2) | Median survival (months) | Univariable HR (95% CI) | Multivariable HR (95% CI)b |
|---|---|---|---|---|---|
| M1-polarized macrophages | |||||
| Cell density | |||||
| Q1 | 69 | 47.8 (33.2–61.0) | 14.2 | 1.00 (reference) | 1.00 (reference) |
| Q2 | 75 | 109.3 (93.6–125.3) | 11.6 | 1.04 (0.70–1.55) | 0.86 (0.56–1.31) |
| Q3 | 75 | 184.1 (159.0–217.1) | 14.4 | 0.99 (0.67–1.47) | 1.02 (0.68–1.52) |
| Q4 | 73 | 378.7 (304.6–488.3) | 10.5 | 1.05 (0.71–1.56) | 0.76 (0.50–1.16) |
| Ptrend | 0.863 | 0.254 | |||
| Gtumor:M1, 20μm radius | |||||
| Q1 | 71 | 0.03 (0.02–0.04) | 14.3 | 1.00 (reference) | 1.00 (reference) |
| Q2 | 74 | 0.06 (0.05–0.07) | 13.8 | 1.29 (0.87–1.92) | 1.22 (0.80–1.84) |
| Q3 | 73 | 0.10 (0.09–0.11) | 11.5 | 1.17 (0.78–1.74) | 1.11 (0.72–1.71) |
| Q4 | 74 | 0.18 (0.15–0.23) | 10.3 | 1.35 (0.91–1.98) | 1.10 (0.72–1.68) |
| Ptrend | 0.222 | 0.939 | |||
| M2-polarized macrophages | |||||
| Cell density | |||||
| Q1 | 71 | 37.3 (20.9–51.3) | 12.0 | 1.00 (reference) | 1.00 (reference) |
| Q2 | 73 | 103.7 (83.9–119.5) | 15.9 | 0.75 (0.50–1.11) | 0.70 (0.46–1.06) |
| Q3 | 75 | 192.5 (167.1–225.5) | 13.5 | 0.90 (0.61–1.32) | 1.05 (0.71–1.56) |
| Q4 | 73 | 353.0 (297.9–479.3) | 9.9 | 1.20 (0.84–1.76) | 1.32 (0.90–1.94) |
| Ptrend | 0.149 | 0.035 | |||
| Gtumor:M2, 20μm radius | |||||
| Q1 | 73 | 0.009 (0.005–0.014) | 15.1 | 1.00 (reference) | 1.00 (reference) |
| Q2 | 73 | 0.03 (0.02–0.03) | 11.1 | 1.41 (0.94–2.11) | 1.23 (0.81–1.88) |
| Q3 | 73 | 0.06 (0.05–0.07) | 10.1 | 1.52 (1.02–2.26) | 1.55 (1.01–2.39) |
| Q4 | 73 | 0.13 (0.11–0.18) | 10.2 | 1.83 (1.25–2.70) | 1.72 (1.14–2.60) |
| Ptrend | 0.004 | 0.009 | |||
The densities of myeloid immune cell subsets are based on the overall densities in tumor area (intraepithelial + stromal). M1-polarized macrophages were defined as macrophages in the 4th and M2-polarized macrophages as macrophages in the 1st quartile of M1-M2-index distribution.
Cox proportional hazards regression model adjusted for age, sex, pathologic N stage (N0, N1, Nx), tumor grade (well/moderately differentiated, poorly-differentiated, unknown), lymphovascular invasion (negative, positive, unknown), resection margin status (R0, R1, R2, unknown), receipt of perioperative treatment.
Abbreviations: CI:confidence interval; HR:hazard ratio; IQR:interquartile range; Q:quartile