American Association for Cancer Research
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FIGURE 4 from Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia

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posted on 2023-07-17, 14:20 authored by Claire E. Pillsbury, Jodi Dougan, Jennifer L. Rabe, Jairo A. Fonseca, Chengjing Zhou, Alyssa N. Evans, Hasan Abukharma, Ona Ichoku, Gloria Gonzalez-Flamenco, Sunita I. Park, Ahmed Aljudi, Deborah DeRyckere, Sharon M. Castellino, Sarwish Rafiq, Solomon Langermann, Linda N. Liu, Curtis J. Henry, Christopher C. Porter

B-ALL cells release secreted/soluble Sig15 that circulates in plasma and inhibits activation of CAR-expressing Jurkat cells. A, sSIG15 detected via electrochemiluminescence (MSD) from the supernatant of REH cells treated for 24 hours with combinations of PMA (81 nmol/L), BOT64 (10 μmol/L), and CSA (1 μmol/L). Dotted line represents the assay limit of detection (10 pg/mL). PMA induces a calcineurin-dependent increase in the release of sSig15. B, sSIG15 detected via MSD from the plasma of pediatric patients with B-ALL, AML or T-ALL and healthy controls (sample size in parentheses). Pediatric patients with B-ALL showed higher plasma concentration of sSIG15 than healthy donors (****, P < 0.0001). C, Cytokines were measured in the plasma from children with leukemia using Luminex and compared with sSig15. Pearson correlation of a subset is depicted graphically using the nearest neighbor algorithm (*, P < 0.05). D and E, Jurkat cells expressing CD19-CAR constructs cultured alone (UT = untreated) or cocultured with CD19+ REH B-ALL cells (REH) at an effector:target ratio of 2:1 with or without 50 μg/mL protein control (Ctrl = human IgG) or recombinant Sig15 (rSig15) for 4 hours and stained for early activation markers CD69 and PD-1. D, Representative contour plots of flow cytometry data. E, Quantification of four independent experiments. Recombinant Sig15 inhibits early Jurkat activation when in coculture with B-ALL cells.


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We demonstrate that Sig15 is overexpressed in hematologic malignancies driven by NFκB, is required for immune evasion in a mouse model of leukemia, and, for the first time, that it circulates at high levels in the plasma of children with leukemia.