Automated assessment of CD8(+) T-lymphocytes and stroma fractions complement conventional staging of colorectal cancer

BACKGROUND: Tumor development is critically dependent on the supporting stroma consisting of inflammatory cells and fibroblasts. This study intended to improve prognostic prediction for early colorectal cancer (CRC) by combined estimation of T-lymphocyte and stroma fractions with conventional markers. METHODS: In total 509 and 1041 stage II/ΙΙΙ CRC from the VICTOR and QUASAR 2 trials were included as a training set and a validation set, respectively. Intratumoral CD8(+) T-lymphocytes and stroma were identified and quantified by machine-based learning on digital sections. The primary endpoint was to evaluate the prognostic value of the combined marker for time to recurrence (TTR). FINDINGS: For low-risk patients (n = 598; stage Ⅱ, and stage ΙΙΙ pT1-3 pN1 with neither lymphatic (L(−)) nor vascular (V(−)) invasion), low stroma fraction (n = 511) identified a good prognostic subgroup with 5-year TTR of 86% (95% CI 83–89), versus the high stroma subgroup TTR of 78% (HR = 1.75, 95% CI 1.05–2.92; P = 0.029). For high-risk patients (n = 394; stage ΙΙΙ pT3 pN1 L(+)/V(+), pT4, or pN2), combined low CD8(+) and high stroma fraction identified a poor prognostic subgroup (n = 34) with 5-year TTR of 29% (95% CI 17-50), versus the high CD8(+) fraction and low stroma fraction subgroup (n = 138) of 64% (HR = 2.86, 95% CI 1.75–4.69; P < 0.001). INTERPRETATION: Quantification of intratumoral CD8(+) T-lymphocyte and stroma fractions can be combined with conventional prognostic markers to improve patient stratification.