Table 2.
Densities of intraepithelial and stromal immune cells and patient survival with inverse probability weighting (IPW)
| Colorectal cancer-specific survival | Overall survival | ||||||
|---|---|---|---|---|---|---|---|
| No. of cases | No. of events | Univariable HR (95% CI)* | Multivariable HR (95% CI)*,† | No. of events | Univariable HR (95% CI)* | Multivariable HR (95% CI)*,† | |
| Tumor intraepithelial region | |||||||
| Lymphocyte density | |||||||
| C1 | 234 | 94 | 1 (referent) | 1 (referent) | 162 | 1 (referent) | 1 (referent) |
| C2 | 233 | 72 | 0.72 (0.52–0.99) | 0.77 (0.56–1.07) | 139 | 0.83 (0.64–1.08) | 0.83 (0.65–1.07) |
| C3 | 234 | 64 | 0.68 (0.49–0.96) | 0.73 (0.52–1.02) | 130 | 0.79 (0.61–1.03) | 0.77 (0.59–1.01) |
| C4 | 233 | 60 | 0.58 (0.41–0.82) | 0.68 (0.48–0.98) | 141 | 0.82 (0.63–1.06) | 0.73 (0.56–0.94) |
| Ptrend‡ | 0.002 | 0.029 | 0.11 | 0.013 | |||
| Plasma cell density | |||||||
| C1 | 343 | 123 | 1 (referent) | 1 (referent) | 227 | 1 (referent) | 1 (referent) |
| C2 | 196 | 42 | 0.54 (0.37–0.77) | 0.53 (0.36–0.76) | 105 | 0.65 (0.50–0.83) | 0.67 (0.52–0.86) |
| C3 | 199 | 64 | 0.92 (0.66–1.26) | 0.96 (0.69–1.33) | 115 | 0.88 (0.69–1.12) | 0.93 (0.73–1.20) |
| C4 | 196 | 61 | 0.82 (0.59–1.14) | 0.77 (0.55–1.08) | 125 | 0.88 (0.68–1.13) | 0.87 (0.68–1.12) |
| Ptrend‡ | 0.44 | 0.36 | 0.44 | 0.48 | |||
| Neutrophil density | |||||||
| C1 | 372 | 137 | 1 (referent) | 1 (referent) | 246 | 1 (referent) | 1 (referent) |
| C2 | 188 | 57 | 0.79 (0.57–1.09) | 1.10 (0.81–1.51) | 111 | 0.77 (0.59–0.99) | 0.96 (0.76–1.21) |
| C3 | 187 | 49 | 0.64 (0.46–0.90) | 0.74 (0.51–1.06) | 107 | 0.67 (0.52–0.87) | 0.70 (0.54–0.91) |
| C4 | 187 | 47 | 0.63 (0.44–0.90) | 0.67 (0.46–0.97) | 108 | 0.73 (0.57–0.93) | 0.67 (0.52–0.87) |
| Ptrend‡ | 0.003 | 0.012 | 0.002 | < 0.001 | |||
| Eosinophil density | |||||||
| C1 | 482 | 171 | 1 (referent) | 1 (referent) | 316 | 1 (referent) | 1 (referent) |
| C2 | 150 | 40 | 0.62 (0.43–0.88) | 0.64 (0.42–0.98) | 84 | 0.72 (0.54–0.95) | 0.80 (0.61–1.07) |
| C3 | 151 | 40 | 0.73 (0.51–1.05) | 0.73 (0.50–1.06) | 87 | 0.87 (0.68–1.11) | 0.80 (0.61–1.04) |
| C4 | 151 | 39 | 0.71 (0.49–1.03) | 0.82 (0.58–1.16) | 85 | 0.75 (0.57–0.99) | 0.81 (0.62–1.06) |
| Ptrend‡ | 0.027 | 0.084 | 0.030 | 0.044 | |||
| Tumor stromal region | |||||||
| Lymphocyte density | |||||||
| C1 | 233 | 110 | 1 (referent) | 1 (referent) | 173 | 1 (referent) | 1 (referent) |
| C2 | 234 | 66 | 0.54 (0.39–0.74) | 0.64 (0.46–0.88) | 132 | 0.64 (0.49–0.83) | 0.64 (0.49–0.83) |
| C3 | 233 | 60 | 0.49 (0.35–0.68) | 0.59 (0.42–0.83) | 134 | 0.64 (0.50–0.83) | 0.66 (0.51–0.85) |
| C4 | 234 | 54 | 0.43 (0.31–0.61) | 0.51 (0.36–0.71) | 133 | 0.59 (0.45–0.77) | 0.56 (0.43–0.72) |
| Ptrend‡ | < 0.001 | < 0.001 | < 0.001 | < 0.001 | |||
| Plasma cell density | |||||||
| C1 | 233 | 88 | 1 (referent) | 1 (referent) | 156 | 1 (referent) | 1 (referent) |
| C2 | 234 | 86 | 1.01 (0.74–1.38) | 0.95 (0.70–1.30) | 150 | 1.03 (0.79–1.34) | 1.01 (0.78–1.31) |
| C3 | 233 | 55 | 0.62 (0.44–0.89) | 0.56 (0.39–0.78) | 127 | 0.79 (0.61–1.03) | 0.72 (0.55–0.93) |
| C4 | 234 | 61 | 0.61 (0.43–0.86) | 0.61 (0.43–0.86) | 139 | 0.78 (0.61–1.01) | 0.73 (0.57–0.93) |
| Ptrend‡ | < 0.001 | < 0.001 | 0.016 | 0.002 | |||
| Neutrophil density | |||||||
| C1 | 234 | 96 | 1 (referent) | 1 (referent) | 169 | 1 (referent) | 1 (referent) |
| C2 | 233 | 68 | 0.71 (0.51–0.99) | 0.88 (0.64–1.23) | 135 | 0.67 (0.52–0.88) | 0.81 (0.62–1.06) |
| C3 | 234 | 67 | 0.66 (0.48–0.91) | 0.88 (0.64–1.22) | 130 | 0.67 (0.52–0.86) | 0.79 (0.61–1.01) |
| C4 | 233 | 59 | 0.55 (0.39–0.78) | 0.67 (0.47–0.96) | 138 | 0.64 (0.51–0.82) | 0.67 (0.51–0.87) |
| Ptrend‡ | < 0.001 | 0.034 | < 0.001 | 0.003 | |||
| Eosinophil density | |||||||
| C1 | 233 | 95 | 1 (referent) | 1 (referent) | 161 | 1 (referent) | 1 (referent) |
| C2 | 234 | 79 | 0.90 (0.66–1.23) | 0.88 (0.65–1.19) | 147 | 0.89 (0.69–1.14) | 0.87 (0.67–1.11) |
| C3 | 234 | 68 | 0.73 (0.52–1.01) | 0.73 (0.52–1.02) | 146 | 0.84 (0.65–1.07) | 0.92 (0.71–1.19) |
| C4 | 233 | 48 | 0.47 (0.32–0.67) | 0.49 (0.34–0.71) | 118 | 0.59 (0.45–0.76) | 0.63 (0.48–0.82) |
| Ptrend‡ | < 0.001 | < 0.001 | < 0.001 | 0.002 | |||
IPW was applied to reduce a bias due to the availability of tumor tissue after cancer diagnosis (see “Statistical Analysis” subsection for details).
The multivariable Cox regression model initially included sex, age, year of diagnosis, family history of colorectal cancer, tumor location, tumor differentiation, disease stage, microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long-interspersed nucleotide element-1 methylation level. A backward elimination with a threshold P of 0.05 was used to select variables for the final models.
Ptrend value was calculated across the four ordinal categories of the density of each immune cell within tumor epithelial and stromal regions in the IPW-adjusted Cox regression model.
Abbreviations: CI, confidence interval; HR, hazard ratio; IPW, inverse probability weighting.