SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer
Claudia Winkler, … , Elisabetta Leo, Gabriele Zoppoli
Claudia Winkler, … , Elisabetta Leo, Gabriele Zoppoli
Published September 22, 2021
Citation Information: JCI Insight. 2021;6(18):e146098. https://doi.org/10.1172/jci.insight.146098.
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Research Article Cell biology Oncology

SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer

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.

Authors

Claudia Winkler, Matthew King, Julie Berthe, Domenico Ferraioli, Anna Garuti, Federica Grillo, Jaime Rodriguez-Canales, Lorenzo Ferrando, Nicolas Chopin, Isabelle Ray-Coquard, Oona Delpuech, Darawan Rinchai, Davide Bedognetti, Alberto Ballestrero, Elisabetta Leo, Gabriele Zoppoli

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Figure 6

SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer cell–intrinsic functional dispositions associated with sensitivity to platinum treatment.

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SLFN11 is a dual biomarker capturing simultaneously interconnected immun...
(A) Bubble chart representing significantly enriched pathways during treatment with cisplatin in SLFN11hi (n = 3) versus SLFN11lo (n = 4) ovarian cancer cell lines. The bubble size indicates the q value (FDR), whereas the color represents the direction of the change as normalized enrichment score (NES), with red indicating a positive enrichment of the comparison and blue a negative one. c, concentration. (B) Heatmap of log fold changes of selected immune-related transcripts for the comparison between the SLFN11hi and SLFN11lo cancer cell lines at the same time points as for A. (C) PBMCs were incubated with IFN-β, GM-CSF, or anti-CD3/CD28 beads for 24 hours and immunoblotted as indicated. Chart shows SLFN11 densitometry (n = 4). (D) DU145 parental or SLFN11-KO cells were stained with/without anti-SLFN11 and analyzed by flow cytometry. (E) PBMCs were treated as in C and analyzed by flow cytometry. FACS plots show SLFN11 and CD25 expression in naive (top) and anti-CD3/CD28-stimulated (bottom) cultures. Charts show quantification of SLFN11hi CD4+ and CD8+ T cells (top) and CD25 expression in SLFN11hi/SLFN11lo T cells (bottom). (F) Purified CD3+ T cells were stimulated with anti-CD3/CD28 beads and immunoblotted as indicated. Chart shows SLFN11 densitometry (n = 4). (G) PBMCs were treated as in C and analyzed by flow cytometry for SLFN11 and programed cell death ligand 1 (PD-L1) expression in myeloid cells. Chart shows quantification of SLFN11hi myeloid cells (n = 8). The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. All data in graphs are presented as mean ± SEM. Statistics by Student’s t test, pairwise comparisons with the 2-tailed t test with reported P values adjusted for family-wise error using the Holm’s method. *P < 0.05; **P < 0.01; ****P < 0.0001.