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 3

STING activation in MPNST increases T cell infiltration and impedes tumor growth.

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STING activation in MPNST increases T cell infiltration and impedes tumo...
(A) Paraffin sections of MPNSTs harvested from vehicle-treated or ADU-S100–treated cisNP mice were stained with antibodies against CD3, CD4, CD8α, PD-1, and PD-L1 and (B) quantified. (C) The same sections were also stained for CD20 and iNOS. (D and E) Tumor volume change with time in response to indicated treatments. (F) Coimmunostaining for CD3 and PD-1 with quantification. Cells marked with asterisks in each panel are magnified and shown adjacently. Control, n = 4; ADU-S100, n = 5. Scale bars: 50 μm. Original magnification, ×80 (enlarged insets in A and C) and ×160 (enlarged insets in F). Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired, 2-tailed t test versus vehicle control. See Methods for a detailed description of the staining methodology.