Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma

Baird, Jason R.; Bell, R. Bryan; Troesch, Victoria; Friedman, David J.; Bambina, Shelly; Kramer, Gwen; Blair, Tiffany C.; Medler, Terry R.; Wu, Yaping; Sun, Zhaoyu; Gruijl, Tanja D. de; Ven, Rieneke van de; Leidner, Rom S.; Crittenden, Marka R.; Gough, Michael

doi:10.1158/0008-5472.can-18-1652

Cited by 51 publications

(49 citation statements)

References 40 publications

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“…40). IL-10 was identified as a prominent immunosuppressive factor in MOC2-derived tumors (41); thus, we additionally assessed the transcription levels of IL-10. We found that IL-10 was trending decreased in the NLRX1-deficient tumors (P = 0.08) (Supplemental Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…Our recent unbiased screen using HNSCC cell-effector immune cell coculture identified the IFN-I pathway as a central signal that maintains HNSCC sensitivity to immune killing (14). IFN-I downstream cytokines and chemokines improve APC and effector trafficking to the tumor mass and maintain a TME that favors APC maturation and cross-priming of CD8 + CTLs (16,19,22,41,(46)(47)(48)(49), thereby driving antitumor immunity. A number of strategies are being assessed to activate STING-mediated innate immune sensing and enhance immune priming.…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition of either ataxia telangiectasia-mutated protein (ATM) or ataxia telangiectasia-and Rad3-related protein (ATR), 2 essential signaling components of the DNA damage response pathway, can induce IFN-I signaling and prime tumors for checkpoint blockade (51,52). Cotargeting immunosuppressive pathways, such as IL-10 signaling, can also improve IFN-I-mediated antitumor activity (41). However, as we show in this study, HPV16 E7 functions as a rheostat for IFN-I signaling, which likely limits the cancer cell-specific response to the aforementioned neoadjuvant therapies.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

Luo¹,

Donnelly²,

Gong³

et al. 2020

Journal of Clinical Investigation

117

121

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

Luo¹,

Donnelly²,

Gong³

et al. 2020

Journal of Clinical Investigation

117

121

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“…Advantages of DDS include their ability to profoundly alter and improve drug pharmacokinetics, provide targeted drug delivery, and therefore alleviate TRAEs whilst enhancing therapeutic outcomes [ 125 , 126 , 127 , 128 ]. The three main DDS discussed here are liposomes, polymers and hydrogels ( Table 3 ) [ 14 , 123 , 124 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]. Liposomes are cationic lipid structures with an aqueous core, making them great candidates for encapsulating negatively charged, hydrophilic CDN compounds [ 138 , 139 , 140 ].…”

Section: Future Directionsmentioning

confidence: 99%

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Aval

Pease

Sharma

et al. 2020

JCM

154

130

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Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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“…Relative to the free controls, the loaded hydrogel at the resection site significantly inhibited local 4T1 breast cancer recurrence and removed the metastases, by increasing the DC, T cell and NK cell amounts and type I IFN secretion. Similarly, Gough et al mixed CDA in phosphate‐buffered saline buffer with Matrigel at 4°C and dropped the liquid into the resection site . At body temperature, the liquid formed an amorphous solid gel.…”

Section: Sting Agonistsmentioning

confidence: 99%

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

Zhao

et al. 2019

Medicinal Research Reviews

110

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Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction.Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. K E Y W O R D S agonist, cyclic dinucleotides, immunotherapy, inhibitor, STING

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Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma

Cited by 51 publications

References 40 publications

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

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