IFN signaling is associated with radiotherapy response in malignant peripheral nerve sheath tumors
Iowis Zhu, Julian Chien, Gabriel E. Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E. Braunstein, Mark D. Adams, Line Jacques, Melike Pekmezci, S. John Liu, Harish N. Vasudevan
Iowis Zhu, Julian Chien, Gabriel E. Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E. Braunstein, Mark D. Adams, Line Jacques, Melike Pekmezci, S. John Liu, Harish N. Vasudevan
View: Text | PDF
Research Article Genetics Immunology Oncology

IFN signaling is associated with radiotherapy response in malignant peripheral nerve sheath tumors

Abstract

Patients with malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. The responses to radiotherapy (RT) are mixed, and the biologic mechanisms underlying this heterogeneity in the radiation response of MPNSTs are not understood. Here, we combined bulk and single-cell transcriptomics, genome-wide CRISPR interference screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and patients’ samples to understand the mediators of the radiation response. Our data revealed that MPNSTs, but not benign plexiform neurofibromas, induced a type I IFN signature that functionally mediated the radiation response. Moreover, irradiation of immunocompetent mouse MPNST allografts led to IFN-mediated T cell recruitment and activation. Both host mouse T cells and intact tumor IFN receptor signaling were required for RT’s efficacy in mouse MPNST allografts. Analysis of human MPNST resection specimens demonstrated that increased microenvironmental and CD8+ T cell infiltration were associated with improved local control following RT. These results provide a preclinical rationale for combining immunomodulatory agents targeting IFN signaling to improve radiation responses in MPNSTs and potentially other soft tissue sarcomas.

Authors

Iowis Zhu, Julian Chien, Gabriel E. Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E. Braunstein, Mark D. Adams, Line Jacques, Melike Pekmezci, S. John Liu, Harish N. Vasudevan

×

Figure 5

IFN activation and T cell recruitment are critical mediators of the MPNST RT response in vivo.

Options: View larger image (or click on image) Download as PowerPoint
IFN activation and T cell recruitment are critical mediators of the MPNS...
(A). Breakdown of cell cluster composition by experimental groups reveals that only cluster 6 T/NK cells were significantly enriched in irradiated tumors (*P < 0.05, 2-sided Student’s t test). (B) Flow cytometric analysis showing the percentage of CD3+ cells that were also CD4+ between the experimental group (top) and the percentage of CD3+ cells that were also PD-1+ between experimental groups (bottom) revealed enrichment of both cell populations in irradiated tumors (*P < 0.05, 2-sided Student’s t test). (C) Differential gene expression analysis of irradiated versus control cluster 6 T cells and NK cells followed by GO biological process and Cytoscape visualization of STRING network of RT-induced genes in cluster 6 reveals upregulation of T cell receptor–based (TCR-based) T cell activation (D) Increased M1 macrophage polarization as shown by violin plots of IFN gene signatures and M1 macrophage gene signatures. (E) Radiation responses in JW18.2 or JW23.3 MPNST subcutaneous allografts implanted into athymic nude mice revealed that T cells were required for the radiation response. (F) JW23.3 sgIfnar1-deficient MPNST cells did not respond to radiation therapy. *P < 0.05 and ***P < 0.001 versus the sgNTC no-RT control, by Dunnett’s multiple-comparison test.