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TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in
Brian J Francica1,2, Ali Ghasemzadeh2,3, Anthony L Desbien1
1Aduro Biotech, Berkeley, California.
Abstract:
The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422-33. ©2018 AACR.
Insights
STING agonists trigger anti-tumor immunity by activating both immune and stromal cells. This crosstalk is crucial for tumor rejection and clearance, offering new insights for STING agonist cancer therapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- The cyclic guanosine monophosphate-AMP (cGMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and initiates immune responses.
- Cyclic dinucleotide (CDN) STING agonists administered intratumorally (i.t.) induce anti-tumor immunity, but the underlying mechanisms involving stromal cells are not fully understood.
Purpose of the Study:
- To elucidate the roles of stromal and immune cells in STING agonist-mediated tumor rejection.
- To investigate the cellular mechanisms driving tumor regression following i.t. CDN administration.
Main Methods:
- Utilized knockout and bone marrow chimeric mouse models.
- Administered intratumoral cyclic dinucleotides (CDNs) to assess tumor responses.
- Analyzed the contribution of STING signaling in stromal cells and TNFα from bone marrow-derived cells.
Main Results:
- STING agonist treatment induced tumor necrosis and rejection through a mechanism involving both stromal and immune cells.
- Bone marrow-derived TNFα was essential for CDN-induced tumor necrosis.
- STING signaling within radioresistant stromal cells was critical for tumor rejection after i.t. CDN administration.
- Demonstrated crosstalk between stromal and hematopoietic cells during CDN-mediated tumor regression.
Conclusions:
- STING agonist-mediated tumor rejection requires the coordinated action of both stromal and immune cells.
- Stromal STING signaling plays a vital role in anti-tumor immune responses initiated by CDNs.
- These findings provide critical mechanistic insights for the clinical development of STING agonists in cancer therapy.
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