The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

Abstract

SummaryHigh-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T-and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

“…Consistent with this, we (Zhang et al, 2018) and others (Safonov et al, 2017) have reported negative associations between immune cell infiltration and intratumoral heterogeneity.…”

“…mRNA vs DNA). Given recent work from our group and others linking increased intratumoral heterogeneity with decreased immune cell infiltration (Safonov et al, 2017;Zhang et al, 2018), one could speculate that stemness might enable intratumoral heterogeneity by both increasing the replicative capacities of individual tumor clones and by shielding antigenic clones from elimination by the immune system.…”

“…We did not, however, find an association between stemness and intratumoral heterogeneity in this cohort (P > 0.05), although the sample size for this analysis was even more limited (N = 25 samples from 6 patients with available data). Additionally, we previously subjected samples from this cohort to Getis-Ord Gi* 'hotspot' analysis to quantify immune cell engagement with tumor cells (Zhang et al, 2018). Intriguingly, all hotspot metrics showed clear negative association with stemness (mixed effects models; P < 0.01; 44 samples from 12 patients; Figure 3D (Nawaz et al, 2015); FCI shown), suggesting that stemness negatively influences lymphocyte engagement with tumor cells.…”

“…Finally, we evaluated a small cohort of high-grade serous ovarian cancer (HGSC) cases (Zhang et al, 2018) for which matched IHC-based T cell counts and microarray-based gene expression data were available for multiple tumor sites within each patient (N = 44 samples from 12 patients). Consistent with the above findings, we found negative association between stemness and total CD3+ T cells (negative binomial mixed effects model; P = 0.042; Figure 3C).…”

Computed Tomography Measures of Inter-site tumor Heterogeneity for Classifying Outcomes in High-Grade Serous Ovarian Carcinoma: a Retrospective Study

“…Acquisition of 5 resistance may be related to specific mutational processes that drive genomic 6 heterogeneity [4,5] and clonal evolution [6,7]. HGSOC exhibits marked intra-site and 7 inter-site genetic heterogeneity across metastatic sites in the peritoneal cavity [5-7] with 8 altered immunological infiltrates and tumor microenvironments [8]. Detection of spatial or 9 temporal heterogeneity by multiple sampling in a single patient is expensive, invasive, and 10 often clinically impractical.…”