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Schlafen 5 is an intracellular immune checkpoint and controls IFN responses in pancreatic ductal adenocarcinoma
Mariafausta Fischietti, Markella Zannikou, Elspeth M. Beauchamp, Diana Saleiro, Aneta H. Baran, Briana N. Hryhorysak, Jamie N. Guillen Magaña, Emely Lopez Fajardo, Gavin T. Blyth, Brandyn A. Castro, Jason M. Miska, Catalina Lee-Chang, Priyam Patel, Elizabeth T. Bartom, Masha Kocherginsky, Frank Eckerdt, Leonidas C. Platanias
Mariafausta Fischietti, Markella Zannikou, Elspeth M. Beauchamp, Diana Saleiro, Aneta H. Baran, Briana N. Hryhorysak, Jamie N. Guillen Magaña, Emely Lopez Fajardo, Gavin T. Blyth, Brandyn A. Castro, Jason M. Miska, Catalina Lee-Chang, Priyam Patel, Elizabeth T. Bartom, Masha Kocherginsky, Frank Eckerdt, Leonidas C. Platanias
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Research Article Cell biology Oncology

Schlafen 5 is an intracellular immune checkpoint and controls IFN responses in pancreatic ductal adenocarcinoma

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Abstract

We provide evidence that human and murine Schlafen 5 (SLFN5) proteins are modulators of type I IFN responses and the immune response in pancreatic ductal adenocarcinoma (PDAC). Blocking expression of Slfn5 in PDAC enhanced IFN responses, suppressed tumor growth, and prolonged survival in immunocompetent mice. Notably, immunophenotypic analysis revealed a reduction in tumor-associated macrophages alongside an increase in tumor-infiltrating effector cells in tumors over time. These findings suggest SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of therapies for PDAC and possibly other malignancies.

Authors

Mariafausta Fischietti, Markella Zannikou, Elspeth M. Beauchamp, Diana Saleiro, Aneta H. Baran, Briana N. Hryhorysak, Jamie N. Guillen Magaña, Emely Lopez Fajardo, Gavin T. Blyth, Brandyn A. Castro, Jason M. Miska, Catalina Lee-Chang, Priyam Patel, Elizabeth T. Bartom, Masha Kocherginsky, Frank Eckerdt, Leonidas C. Platanias

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Figure 3

IFN-α enhances the anti-PDAC effects of Slfn5 targeting.

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IFN-α enhances the anti-PDAC effects of Slfn5 targeting.
(A) KPC1199 luc...
(A) KPC1199 luciferase-expressing Slfn5-WT or Slfn5-KO cells (5 × 104 cells/mouse) were injected into the pancreatic tails of male and female C57BL/6J mice. Mice were randomized into the following treatment groups: Slfn5 WT PBS (n = 7), Slfn5 WT IFN-α (n = 7), Slfn5 KO PBS (n = 7), and Slfn5 KO IFN-α (n = 8). Where indicated, mice were injected subcutaneously with 600 ng murine IFN-α per mouse once per week for 2 weeks. Tumor growth was monitored at least once per week by bioluminescence imaging (BLI). Normalized BLI values are shown. On day 17, model-based estimate of the mean difference in BLI signal between WT IFN-α and Slfn5-KO IFN-α was 3.91 × 109 photons/s/cm2/sr (95% CI 1.72 × 109 to 6.09 × 109). Two-way ANOVA with Šidák’s multiple-comparison test for day 17. Comparison of BLI signals on day 17 is based on mixed-effects model up to day 17. Data are expressed as mean ± SEM of tumor BLI signals for each genotypic treatment group; ****P < 0.0001. (B) Survival curves of mice bearing Slfn5-WT and Slfn5-KO pancreatic tumors. Survival was estimated using the method of Kaplan-Meier and groups were compared using the log-rank test; **P < 0.01; ***P < 0.001; ****P < 0.0001. (C) Median survival time (days) for indicated genotypic treatment groups was estimated using Simple Survival Analysis (Kaplan-Meier) in GraphPad.

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