Objective: Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer.
Methods: The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8 T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses.
Results: The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression.
Conclusions: The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.