Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy

Abstract

Intratumoral immune cells and ERCC1 expression are likely to play a role in the response of ovarian carcinoma to chemotherapy, but their impact on therapy outcome is still unclear. Therefore, 41 cases of optimally resected high grade serous ovarian carcinomas were examined retrospectively for stromal and intraepithelial lymphocyte populations and ERCC1 status in relation to response to platinum-based therapy. Based on RECIST criteria, 27 patients were classified as responsive and 14 as therapy resistant, respectively. Using immunohistochemistry for CD3, CD8, CD4, TIA1, MUM1 and FOX P3 on representative tumor sections, we quantitatively evaluated the intratumoral density of lymphocyte subpopulations. In addition, ERCC1 protein and mRNA expression were determined by immunohistochemistry using the Steffensen score and quantitative RT-PCR, respectively. Furthermore, ERCC1 SNP's C8092A and codon 118 were analysed. Response to chemotherapy was significantly associated with higher numbers of stromal CD3+ (mean 21.33 lymphocytes/HPF versus 8.21 lymphocytes/HPF, p = 0.002) and CD8+ lymphocytes (mean 9.22 lymphocytes/HPF versus 4.57 lymphocytes/HPF, p = 0.013). Counts of intraepithelial CD3+ and CD8+ lymphocytes, stromal and intraepithelial FOXP3+ and TIA1+ cells, CD4+ lymphocytes, and MUM1+ plasma cells did not reach statistical significance. Neither ERCC1 protein expression (p = 0.232) nor SNPs codon 118 and C8092A of the ERCC1 gene (p = 0.269 and p = 0.543) showed an association with therapy response. The same was true for ERCC1 mRNA levels (p = 0.896), probably due to intratumoral lymphocyte contamination. In conclusion, the density of CD3+ and CD8+ T-cells in tumor stroma proved to be a significant predictor for response to platinum-based therapy, whereas examination of ERCC1 failed to identify therapy-responsive patients.

BTN3A2 Expression in Epithelial Ovarian Cancer Is Associated with Higher Tumor Infiltrating T Cells and a Better Prognosis

“…The first reported observation [35] found that CD3 + T cells were associated with better survial and disease-free-progression in a cohort containing several subtypes of EOC. While some studies confirmed the relation between intratumoral CD3+T cells density and EOC patient prognosis [36], [37], [38], others did not [39], [40] [31], [37], [41]. Together, these observations suggest that complex regulatory factors govern tumoral microenvironement and immune function.…”

Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis

“…3). The race of the subjects in the studies from Steffensen et al [17, 20], Bösmüller et al [19], and Moxley et al [10] was Caucasian; whereas the race of the subjects in the studies from Sokbom K et al [18], Qi B et al [11], and Yang et al [21] was Asian. Furthermore, the same ethnicity (Chinese, studied by Qi B et al [11] and Yang Shuying et al [21]) or the same author (Steffensen et al [17, 20]) showed different outcomes.…”

“…On the other hand, the studies of Caucasian population show conflicting results. For example, Steffensen [20] and Bösmüller [19] indicated that the OR was greater than 1, whereas, Smith [16], Steffensen [17] and Moxley [10] did not show significant difference. Moreover, even the same author, Steffensen K.D., had conflicting results in 2011 [20] and 2008 [17].…”

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

“…In fact, higher TIL infiltration has been reported to correlate with better prognosis in many tumor types, [11][12][13][14][15] including ovarian cancer for which a high degree of intratumoral CD8 C T cell was correlated with better clinical response to platinum agents. 16 However, in some cases they may protect cancer cells from the host immune system. The presence of a higher number of regulatory T cells, which suppress tumorÀspecific T cell immunity, was shown to be correlated with poor prognosis in ovarian cancer patients.…”