The Association of Mismatch-Repair (MMR) Deficiency with Tumor Infiltrating Lymphocytes and Survival in Patients with Ovarian Cancer

Objectives: The role of DNA mismatch repair (MMR) deficiency in the pathogenesis and prognosis of ovarian cancer has been a subject of considerable research. Deficiency in MMR genes result in accumulation of thousands of mutations in the genome, leading to a high mutation burden and subsequent activation of the immune system due to an increase in the number of “mutation-derived neoantigens”. It has been increasingly reported that this process results in the number of tumors infiltrating lymphocytes with a favorable impact on prognosis. The aim here is to examine the association of mismatch repair (MMR) deficiency with tumor-infiltrating lymphocytes and other clinical and pathological characteristics in patients with ovarian cancer.
Methods: In a total of 81 patients with ovarian cancer, the microsatellite instability and presence of tumor infiltrating lymphocytes (CD3, CD8, CD4) were examined immunohistochemically. Negative test result in any of the markers MLH-1, MSH-2, MSH-6, or PMS-2 was considered to microsatellite instability (MSI). Also, with regard to tumor infiltrating lymphocytes, a proportion level of greater than 10% was considered positive.
Results: Fifty-one patient (53%) had locally advanced and metastatic disease, and 54 patients (66.7%) had high-grade tumors. Fifty-nine patients (72 %) had serous carcinoma. There was a loss of MMR protein expression in 28 patients (35%), and 53 (65%) were microsatellite stable. There were no significant associations between microsatellite status and age, grade, stage, lymphovascular invasion, CD3, and CD8. Among microsatellite stable patients, CD4 was statistically significantly higher (p=0.03). A reduction in CD3, CD8, and CD4 was found in 53 (64%), 57 (70%), and 54 (66 %) patients, respectively. A significant association between CD3 and lymphovascular invasion was found (p=0.011). CD3 levels are higher in patients with lymphovascular invasion. Survival analysis did not show any relationship between microsatellite instability, progression-free survival, and overall survival. Stage, grade, lymphovascular invasion, Ki-67, and CD8 were significant predictors of progression-free survival (p<0.001, p=0.011, p=0.022, and p=0.02, respectively). Also, there was a significant association between CD4 and overall survival (p=0.007).
Conclusion: We believe that assessment of tumor infiltrating lymphocytes holds the potential to provide valuable prognostic information as well as guidance for management strategies in the clinical practice.