High Density of CD16+ Tumor-Infiltrating Immune Cells in Recurrent Ovarian Cancer Is Associated with Enhanced Responsiveness to Chemotherapy and Prolonged Overall Survival

SIMPLE SUMMARY: The late—and in most cases at an advanced stage—diagnosis of patients with ovarian cancer (OC) and the high recurrence rate make this malignant disease the most lethal among gynecological cancers. With a mortality-to-incidence ratio of 0.74, OC is a tumor with the fifth most frequent progression after esophageal cancer, liver cancer, pancreatic cancer, and brain tumors. The updated FIGO staging system is the gold standard in the clinic and includes surgical, radiologic, and pathologic elements to describe the extent of OC. This system is used to describe tumor extent, plan further therapy, and predict prognosis. However, it is consistently observed that patients with identical stages and treatments have a completely different outcome in terms of survival and recurrence. This fact indicates that this classification alone is not sufficient for the prognosis of OC in the vast majority of cases. Over the last two decades, many studies have demonstrated the critical role of the tumor microenvironment in tumorigenesis, progression, prognosis, and response to chemotherapy. In the current study, we investigate the role of CD16 expression in OC. ABSTRACT: Background: Ovarian cancer (OC) is the most aggressive and fatal malignancy of the female reproductive system. Debulking surgery with adjuvant chemotherapy represents the standard treatment, but recurrence rates are particularly high. Over the past decades, the association between the immune system and cancer progression has been extensively investigated. However, the interaction between chemotherapy and cancer immune infiltration is still unclear. In this study, we examined the prognostic role of CD16 expression in OC, as related to the effectiveness of standard adjuvant chemotherapy treatment. Methods: We analyzed the infiltration by immune cells expressing CD16, a well-characterized natural killer (NK) and myeloid cell marker, in a tissue microarray (TMA) of 47 patient specimens of primary OCs and their matching recurrences by immunohistochemistry (IHC). We analyzed our data first in the whole cohort, then in the primary tumors, and finally in recurrences. We focused on recurrence-free survival (RFS), overall survival (OS), and chemosensitivity. Chemosensitivity was defined as RFS of more than 6 months. Results: There was no significant correlation between CD16 expression and prognosis in primary carcinomas. However, interestingly, a high density of CD16-expressing tumor-infiltrating immune cells (TICs) in recurrent carcinoma was associated with better RFS (p = 0.008) and OS (p = 0.029). Moreover, high CD16 cell density in recurrent ovarian carcinoma showed a significant association with chemosensitivity (p = 0.034). Univariate Cox regression analysis revealed that the high expression of CD16+ TIC in recurrent cancer biopsies is significantly associated with an increased RFS (HR = 0.49; 95% CI 0.24–0.99; p = 0.047) and OS (HR = 0.28; 95% CI 0.10–0.77; p = 0.013). However, this was not independent of known prognostic factors such as age, FIGO stage, resection status, and the number of chemotherapy cycles. Conclusions: The high density of CD16-expressing TICs in recurrent ovarian cancer is associated with a better RFS and OS, thereby suggesting a previously unsuspected interaction between standard OC chemotherapy and immune cell infiltration.