Automated Quantitation of CD8-positive T Cells Predicts Prognosis in Colonic Adenocarcinoma With Mucinous, Signet Ring Cell, or Medullary Differentiation Independent of Mismatch Repair Protein Status

Abstract

Despite their association with DNA mismatch repair (MMR) protein deficiency, colonic adenocarcinomas with mucinous, signet ring cell, or medullary differentiation have not been associated with improved survival compared with conventional adenocarcinomas in most studies. Recent studies indicate that increased T-cell infiltration in the tumor microenvironment has a favorable prognostic effect in colonic adenocarcinoma. However, the prognostic effect of tumor-associated T cells has not been evaluated in histologic subtypes of colonic adenocarcinoma. We evaluated CD8-positive T-cell density in 259 patients with colonic adenocarcinoma, including 113 patients with tumors demonstrating mucinous, signet ring cell, or medullary differentiation, using a validated automated quantitative digital image analysis platform and correlated CD8-positive T-cell density with histopathologic variables, MMR status, molecular alterations, and survival. CD8-positive T-cell densities were significantly higher for MMR protein-deficient tumors (P<0.001), BRAF V600E mutant tumors (P=0.004), and tumors with medullary differentiation (P<0.001) but did not correlate with mucinous or signet ring cell histology (P>0.05 for both). In the multivariable model of factors predicting disease-free survival, increased CD8-positive T-cell density was associated with improved survival both in the entire cohort (hazard ratio=0.34, 95% confidence interval, 0.15-0.75, P=0.008) and in an analysis of patients with tumors with mucinous, signet ring cell, or medullary differentiation (hazard ratio=0.06, 95% confidence interval, 0.01-0.54, P=0.01). The prognostic effect of CD8-positive T-cell density was independent of tumor stage, MMR status, KRAS mutation, and BRAF mutation. Venous invasion was the only other variable independently associated with survival in both the entire cohort and in patients with tumors with mucinous, signet ring cell, or medullary differentiation. In summary, our results indicate that the prognostic value of MMR protein deficiency is most likely attributed to increased tumor-associated CD8-positive T cells and that automated quantitative CD8 T-cell analysis is a better biomarker of patient survival, particularly in patients with tumors demonstrating mucinous, signet ring cell, or medullary differentiation.

CD8-positive T cells and CD204-positive M2-like macrophages predict postoperative prognosis of very high-risk prostate cancer

“…Several studies have been reported that CD8 + cell infiltration is associated with better prognosis 11 , 12 . In other reports, CD8 + cell was also associated with recurrence, progression, or lymph node invasion 13 , 14 .…”

Immune response in colorectal carcinoma: a review of its significance as a predictive and prognostic biomarker

“…Williams et al evaluated 520 colorectal carcinomas with mucinous differentiation and demonstrated that high TILs (defined as ≥ 2 TILs per five high-power fields by manual quantitation) was a predictor of disease-free survival, independent of MMR status, BRAF mutation status and histological grade. 87 Similarly, Hartman et al demonstrated that CD8 + T cell density using quantitative digital image analysis of the tumour centre and invasive margin was an independent predictor of disease-free survival in colonic adenocarcinomas with mucinous differentiation 41 (Figure 4). The data indicate that TILs within adenocarcinomas with mucinous differentiation may be an important prognostic feature.…”

“…Similarly, Hartman et al . demonstrated that CD8 + T cell density using quantitative digital image analysis of the tumour centre and invasive margin was an independent predictor of disease‐free survival in colonic adenocarcinomas with mucinous differentiation 41 (Figure 4). The data indicate that TILs within adenocarcinomas with mucinous differentiation may be an important prognostic feature.…”

“…Automated quantitative digital image analysis using other digital image analysis platforms have also been reported, 15 including using the Aperio image analysis software (Figure 3). 41 In these studies, the invasive margin was defined as 0.5 mm extending into the tumour centre and 1.0 mm beyond the tumour. In contrast to the immunoscore, entire regions of the tumour centre and invasive margin were analysed by digital image analysis, without dividing the areas into smaller tiles.…”

CD8+ T-cell Density Is an Independent Predictor of Survival and Response to Adjuvant Chemotherapy in Stage III Colon Cancer

“…The AUROC for CD8 + T-cell density in the tumor center for the stage II to III cohort was 0.66 (0.59 to 0.73, 95% CI), with an optimal cutoff of 109/mm 2 . Using these cutoffs, the tumors were separated into 3 categories (low, intermediate, and high), as previously described 30. For the survival analyses, the intermediate and high CD8 + T-cell density categories were combined into 1 category (intermediate/high CD8 + T-cell density) given the results of our prior study and those using the immunoscore that demonstrated similar survival for these 2 categories 14,30,31…”