Tumor-infiltrating lymphocytes expression in stage IIIc/IV of high-grade serous ovarian cancer: Variation with neoadjuvant chemotherapy and prognostic value

Abstract

Background: Ovarian cancer is a malignancy with a complex immune suppressive microenvironment mediated by the recruitment or induction of CD4+ regulatory T cell. The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIc/IV of high-grade serous ovarian carcinoma (HGSOC), and its relationship to treatment response. Methods: We retrospectively identified 33 patients diagnosed with HGSOC and treated with neoadjuvant platinum-paclitaxel from 2005-2014. Pre and post-neoadjuvant treatment tissue samples were submitted to immunohistochemical analyses with anti- CD3, CD4 and CD8 antibodies for the identification of tumor-infiltrating lymphocytes (TILs). Pathological response classification to NACT was made according to Steffen Bohm (JCO 2015). Response score system (CRS) was explicitly defined (CRS-1; No or minimal tumor response, CRS-2; Appreciable tumor response amid viable tumor that is readily identifiable, CRS-3; Complete or near-complete response). Results: The average age of patients was 63.44 years (46.53-84.14). BRCA-mutation status was negative in 78.8% of patients (26/33); BRCA-mutation was positive in 6.1% (2/ 33); and variant of uncertain significance was found in 15.1% (5/33). The majority of patients (78.8%) were stage IIIc. The area under the ROC curve of post-surgery TILs for complete pathological response were: CD4 (epithelial): [0.73 (0.5; 0.97), p: 0.084]; CD4 (stromal): [0.74 (0.51; 0.97), p: 0.077] and CD8 (epithelial): [0.81 (0.63; 1.0), p: 0.02]. The expression of epithelial CD4 TILs in pre-surgery samples (≤ 0.5 [OR: 0.7(0.01; 0.86), p: 0.038]) and epithelial CD8 TILs in post-surgery samples (≤5.4 [OR: 0.1(0.01; 1.19, p: 0.06]) proved to be a marker of good prognosis for pathological response. Survival analysis demonstrated that the expression of epithelial CD3 ≤4.3 in pre-surgery samples is a marker of poor prognosis. Conclusions: The high number of tumor-infiltrating lymphocytes in post-surgery samples was significantly associated with higher rates of complete pathological response and better prognosis. It is convenient to carry out further and multicentric studies to validate these results.