Abstract
Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDAs), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens before platinum-based chemotherapy treatment, we show, for the first time to our knowledge, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 was associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in an SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer cell–intrinsic functional dispositions associated with sensitivity to DDA treatment.
Highlights
The putative DNA/RNA helicase Schlafen 11 (SLFN11) was independently reported by us [1] and others as the factor that best correlates with the response of cancer cells to DNA-damaging agents (DDAs) with different modes of action, such as topoisomerase I [2, 3], topoisomerase II inhibitors, and alkylating agents [4,5,6]
Since several studies have reported on the role of tumor-infiltrating lymphocytes (TILs) in the prognosis of ovarian cancer [21,22,23,24], and SLFN11 has been shown to be expressed in primary human T lymphocytes [16], we evaluated TIL infiltration by CD3 and CD8 staining, both in terms of total number and of a measure of TILs in direct contact with cancer cells, without stroma interposition in high-grade serous ovarian carcinoma (HGSOC) [19]
By implementing analytic pipelines in clinical material, we demonstrate, for the first time to our knowledge, that SLFN11 in both the neoplastic and microenvironmental compartments of tumor specimens modulates the response to platinum-containing regimens in patients with HGSOC
Summary
The putative DNA/RNA helicase Schlafen 11 (SLFN11) was independently reported by us [1] and others as the factor that best correlates with the response of cancer cells to DNA-damaging agents (DDAs) with different modes of action, such as topoisomerase I (e.g., topotecan and irinotecan) [2, 3], topoisomerase II inhibitors (e.g., epirubicin), and alkylating agents (e.g., cyclophosphamide or platinum) [4,5,6]. In spite of macroscopically complete resection and upfront CT, most patients with HGSOC will eventually progress and die from their disease In this context, several studies have shown that tumor-infiltrating lymphocytes (TILs), especially CD3+ and CD8+ TILs, may have a role as prognostic biomarkers, but their clinical utility is still unclear [19]. The main aim of our study was to determine whether SLFN11 transcript and protein could be accurately and reproducibly measured in 2 different cohorts of serous ovarian cancer, one internal and another from The Cancer Genome Atlas (TCGA), considering the following aspects: (a) the sensitivity of HGSOC to DDAs, (b) the need for clinically useful prognostic biomarkers for CT treatments, (c) the potential connection between SLFN11 and TILs, and (d) the potential of developing SLFN11 as a biomarker in the clinic, based on results in preclinical models. We aimed to gain mechanistic insights into the link between SLFN11 cancer immunity and DNA-damaging treatment, and most importantly, we investigated whether SLFN11 could represent a relevant prognostic biomarker to platinum-based treatment response in patients with advanced-stage HGSOC
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