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Abstract
Background Ovarian cancer is frequently diagnosed in the advanced stages. These patients usually respond to standard therapy initially, but about eighty percent soon become resistant to platinum based treatments and die within five years.1 2 Also importantly, the overall survival of African American (black) women with high grade serous ovarian cancer (HGSOC) is worse than for Caucasian (white) women.3 4 This is partly due to socioeconomic discrepancies but the biology of the ovarian tumor microenvironment (TME) may also be a major contributing factor to dispartate outcomes between these patient groups. Here we will test the hypothesis that there are differing immune and gene parameters in black and white patients ovarian TME which may predispose black patients to worse survival.
Methods To understand differences between the ovarian TME in patients of different races we used two different methods. Firstly, studies investigated ovarian tumor sections of black and white HGSOC patients. Formalin fixed paraffin embedded (FFPE) sections were stained by immunohistochemistry (IHC) for CD8+ T cells and for myeloid derived suppressor cells (MDSC; CD11b+CD14+CD33+ co-staining by multiplex immunofluorescence). CD8+ T cells in ovarian cancer tissue sections were scored in a semi-quantitative manner using the H-score, which incorporates percentage of cells stained and intensity of staining resulting in a score ranging from 0 lowest to 300 highest. A pilot study was also conducted by NanoString Digital Spatial Profiling to compare differences in gene expression in tissue arrays of black and white HGSOC patients TME.
Results There was a trend towards a lower CD8+ T cell H-score in black patients (70.9, n=8) than in white patients (83.9, n=9) in the ovarian TME, although this difference was non-significant. There were no significant differences in MDSC density in tumors between black and white patients. There were several differentially expressed genes in the ovarian TME of black versus white patients in CD3, CD68 and PanCK ROIs (figure 1).
Conclusions It is known that an increased presence of CD8+ T cells in the ovarian TME is associated with improved ovarian cancer outcome.5 Testing in a larger patient cohort will determine whether there is a significantly different density or distribution of CD8+ T cells between black and white patients in the ovarian TME. Studies are in progress to validate the differentially expressed genes between black and white patients and to correlate with grade of ovarian cancer and survival.
References 1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17–48. doi: 10.3322/caac.21763
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5. Sato E, Olson SH, Ahn J, Bundy B, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005;102:18538–18543.
Comparison of most significant gene differences between black and white patients ovarian TME. A FFPE tissue array was made consisting of ovarian tumor tissue for 3 white patients and 2 black patients with HGSOC and 1 patient with polycystic ovarian disease. Immunofluorescence staining was performed for CD3 (T cells), CD68 (macrophages) and panCK (tumor). Regions of interest (ROI) were selected in the CD3, CD68 and PanCk stained regions of each patient tissue for sequencing on a NanoString Digital Spatial Profiling DSP) platform. Differential analysis between genes was performed by the linear mix model (LNM) using FDR (false discovery rate) < 0.05 as cutoff. (A) volcano plot is for the most significant genes between black and white patients in the CD3 ROIs, (B) in the CD68 ROIs, (C) in the PanCK ROIs. (D) shows the most significant genes in the PanCK region between the white and control patients (273 genes were differentially expressed). There were 175 differentially expressed genes in black versus control patients in the PanCK ROIs (not shown)
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