Abstract 3122: Density of CD3+ and CD8+ tumor-infiltrating T lymphocytes as predictor of survival in colon cancer stage I-III
Authors: Hestetun Kjersti E. , Stanisavljević Luka , Myklebust Mette P. , Dahl Olav 
Published: August 2018

Abstract
Introduction: The risk of recurrence after surgery for colon cancer is not only determined by cancer stage and molecular characteristics, but also by the tumor microenvironment. This study aims to assess the prognostic value of CD3+ and CD8+ T lymphocyte infiltration and the relation to mismatch repair (MMR) deficiency.
Material and methods: The study cohort includes 289 patients with surgically treated colon cancer stage I-III (no adjuvant chemotherapy) with clinical- and follow-up data. Immunohistochemistry for CD3+ and CD8+ T lymphocytes and MMR proteins MLH1, MSH2, MSH 6 and PMS2 was performed on Tissue Micro Arrays. (Results were available from 242/258 patients, respectively). Tumors were characterized as MMR deficient/proficient according to expression pattern. Densities of CD3+ and CD8+ lymphocytes were assessed within the tumor margins (tumor infiltrating lymphocytes, TILs) and stroma &lt;100 μm from tumor margin (stromal lymphocytes) and results were combined into semi-quantitative composite scores. In cases of intratumoral heterogeneity, the cylinder with the highest density of TILs was included in the analyses. Results were dichotomized at the median value into low and high density.
Results: MMR deficiency (60 patients, 24.8%) was significantly associated with high density of CD3+ and CD8+ TILs and stromal lymphocytes (p&lt;0.001, p=0.001 Chi square test), but no independent prognostic value of MMR deficiency was demonstrated in our multivariate models. CD3+ and CD8+ TILs and stromal CD3+ and CD8+ lymphocytes were analyzed in separate multivariate cox regression models adjusting for TNM-stage, sex, age, MMR status, histology and tumor differentiation. Low density of CD3+ and CD8+ TILs was an adverse independent prognostic marker of recurrence in colon cancer stages I-III (HR 4.63, CI 1.72-12.49, p=0.002) and the colon cancer stage III subgroup (HR 4.83, CI 1.06-21.97, p=0.042). TNM-stage and differentiation grade were other statistically significant variables in the colon cancer stage I-III model. The stromal lymphocyte score did not reach statistical significance in our multivariate models. Kaplan Meier plots illustrate marked differences in survival between groups of various TIL densities. The low TIL density group had a mean recurrence-free survival of 50.5 months (SE 1.89) versus 63.5 months (SE 1.11) for patients with high TIL density (p&lt;0.001) in colon cancer stage I-III.
Conclusions: Our results support the prognostic impact of tumor infiltrating CD3+ and CD8+ lymphocyte density in colon cancer stage I-III and indicate that a high TIL density is a stronger predictor of survival than MMR deficiency.
Citation Format: Kjersti E. Hestetun, Luka Stanisavljević, Mette P. Myklebust, Olav Dahl. Density of CD3+ and CD8+ tumor-infiltrating T lymphocytes as predictor of survival in colon cancer stage I-III [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3122.