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

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 5

Slfn5 loss is associated with changes within the immunosuppressive PDAC TME.

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Slfn5 loss is associated with changes within the immunosuppressive PDAC...
(A–J) Immunophenotypic analysis of tumor-bearing pancreases by multicolor flow cytometry. (A, C, E, G, and I) CTRL (n = 10) and Slfn5-KO (n = 9) KPC1199 luciferase-expressing cells (5 × 104 cells/mouse) were injected into the pancreatic tails of C57BL/6J mice and 7 days after cell implantation CTRL and Slfn5-KO tumor–bearing pancreases were harvested and processed for immunophenotypic analysis by multicolor flow cytometry. (B, D, F, H, and J) CTRL (n = 10) and Slfn5-KO (n = 11) KPC1199 luciferase-expressing cells (5 × 104 cells/mouse) were injected into the pancreatic tails of C57BL/6J mice and 21 days after cell implantation CTRL and Slfn5-KO tumor–bearing pancreases were harvested and processed for immunophenotypic analysis by multicolor flow cytometry. Scatter dot plots show the percentage of tumor-infiltrating cells. (A and B) Immunosuppressive cells, i.e., TAMs (left panel), Tregs (middle panel), and TAMCs (right panel). (C and D) Innate myeloid immune cells, i.e., M1 macrophages (left panel) and M2 macrophages (right panel). (E and F) Effector cells, i.e., NK cells (left panel), CD8+ T cells (middle panel), and CD4+ T cells (right panel). (G and H) Activation markers (IFN-γ, GZMB, CD69) of NK cells, and (I and J) of CD8+ cells. Data are expressed as mean ± SEM of percentages of indicated immune infiltrates as detailed in Supplemental Figure 2. Two-tailed unpaired t test with Mann-Whitney test; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.