STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy
Bandarigoda N. Somatilaka, Laasya Madana, Ali Sadek, Zhiguo Chen, Sanjay Chandrasekaran, Renee M. McKay, Lu Q. Le
Bandarigoda N. Somatilaka, Laasya Madana, Ali Sadek, Zhiguo Chen, Sanjay Chandrasekaran, Renee M. McKay, Lu Q. Le
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Research Article Oncology

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy

Abstract

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase–activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell–rich tumor microenvironment. While MPNSTs are noninflamed “cold” tumors, here, we converted MPNSTs into T cell–inflamed “hot” tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

Authors

Bandarigoda N. Somatilaka, Laasya Madana, Ali Sadek, Zhiguo Chen, Sanjay Chandrasekaran, Renee M. McKay, Lu Q. Le

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Figure 1

Characterization of the immune microenvironment of MPNST.

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Characterization of the immune microenvironment of MPNST. (A–D) Paraffin...
(A–D) Paraffin sections of murine spleen, murine pNF (harvested from Sox10-CreERT Nf1fl/fl mice induced with tamoxifen), murine MPNST (from cisNP mice), and MPNST allografts in athymic nude mice (aMPNST) were stained with antibodies against CD3, CD4, and CD8α (A); CD20 (B); and Iba1, iNOS, and the mannose receptor (C). (D) Paraffin sections of human melanoma, murine pNFs, murine MPNSTs, and human MPNSTs (hMPNST) were stained with antibodies against PD-1 and PD-L1. Sections in A–D were counterstained with hematoxylin (blue), and the respective cell counts for A–D are shown on the right. Data indicate the mean ± SEM (A) and the mean ± SD (B–D). *P < 0.0 and ****P < 0.0001, by 2-tailed t test with respect to pNF (A). Scale bars: 50 μm. Original magnification, ×80 (enlarged insets).