High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma

Abstract

Background: The validation of novel prognostic indicators is of greatest interest for the management of esophageal adenocarcinoma (Barrett's cancer), particularly for non-metastasized (stage I-IIA) disease. The prognostic role of tumor infiltrating T-lymphocytes (TILs) in Barrett's cancer has not been reported so far. Here we evaluated the impact of TILs on survival, recurrence, and metastasis in Barrett's cancer, particularly in stage I-IIA patients.

Methods: The levels of the adaptive immune markers CD3, CD8, and CD45RO were analyzed by immunohistochemistry and image analysis in tissue microarrays consisting of tumor tissues of 118 patients with primary resected Barrett's cancer. The findings were correlated with clinicopathological parameters including patient outcome.

Results: In multivariate analysis, a low density of intratumoral CD45RO+ immune cells was an independent unfavorable factor for disease-free survival in stages I-IIA patients (P = 0.004, RR = 4.7, 95% CI = 1.6-13.5) as well in the entire cohort (P = 0.048, RR = 2.0, 95% CI = 1.0-4.0). High CD3+ and CD45RO+ levels were associated with prolonged disease-free survival and overall survival as well with low recurrence rates of disease (P = 0.005 and P = 0.018, respectively). In addition, low CD3+ levels were correlated with a higher frequency of lymph node metastasis (P = 0.025).

Conclusions: This study demonstrates that the density of CD45RO+ TILs is an independent prognostic factor in non-metastasized (stage I-IIA) Barrett's cancer patients and indicates an important role for the adaptive immunologic microenvironment. The inclusion of CD45RO+ density may help to improve the management of stage I-IIA Barrett's cancer.

Figure 1

Kaplan-Meier plots of disease-free (A-C) and overall (D-F) survival in primary resected Barrett's cancer patients according to CD3+ (A and D), CD8+ (B and E), and CD45RO+ (C and F) tumor infiltrating lymphocytes (TILs). In each cohort high and low TIL densities were plotted according to the corresponding cut-off values. Blue lines indicate patients with tumors containing high TIL densities, red lines indicate patients whose tumors had low densities of TILs. P values are calculated by log-rank tests. The 5-year disease-free survival (DFS) rate for patients with high CD3+ levels was 49.2% compared to 23.6% for patients with low levels of CD3+ TILs (overall survival (OS): 54.7% versus 29.7%). Patients with high densities of CD45RO+ TILs had a 5-year DFS rate of 45.7% in contrast to 14.9% for patients with low densities of CD45RO+ (OS: 47.9% versus 24.4%).

Figure 2

Kaplan-Meier plots of disease-free (A) and overall (B) survival in primary resected Barrett's cancer patients as a function of tumor infiltrating lymphocyte (TIL) density. Survival differences were found when high and low densities of CD3+, CD8+, and CD45RO+ were combined. In each cohort high and low TIL densities were plotted according to the corresponding cut-off values. Blue lines indicate patients with tumors containing high CD3+CD8+CD45RO+ densities, red lines indicate patients whose tumors had low densities of CD3+CD8+CD45RO+ TILs. P values are calculated by log-rank tests. The 5-year disease-free survival rate for patients with high levels of CD3+CD8+CD45RO+ TILs was 42.9% compared to 10.0% for patients with low levels of CD3+CD8+CD45RO+ TILs (overall survival: 51.3% versus 11.7%).

Figure 3

Kaplan-Meier plots of disease-free (A and B) and overall (C and D) survival in primary resected Barrett's cancer patients according to CD45RO+ tumor infiltrating lymphocytes (TILs) and lymph node status. (A and C) Survival rates in patients without regional lymph node metastases. (B and D) Survival rates in patients with presence of regional lymph node metastasis. In each cohort high and low TIL densities were plotted according to the corresponding cut-off values. Blue lines indicate patients with tumors containing high CD45RO+ levels, red lines indicate patients whose tumors had low densities of CD45RO+. P values are calculated by log-rank tests. The 5-year disease-free survival (DFS) rate in the group of the patients without lymph node metastases was 69.4% for high CD45RO+ levels compared to 16.7% for patients with low levels of CD45RO+ levels (overall survival (OS): 69.9% versus 41.7%). In the group of the patients with lymph node metastases the 5-year DFS rate was 13.1% for patients with high densities of CD45RO+ in contrast to a rate of 15.6% for patients low densities of CD45RO+ (OS: 18.1% versus 15.3%).