Induction of tumor regression by intratumoral STING agonists combined with anti-programmed death-L1 blocking antibody in a preclinical squamous cell carcinoma model.
Cyclic dinucleotides (CDNs) are bacterial intracellular messengers that have demonstrated antitumor activity in melanoma and breast tumors, although their role in immunotherapy of head and neck squamous cell cancers (HNSCCs) has not been well investigated.



We measured primary tumor growth rates, mechanism of antitumor activity, and efficacy of programmed death-L1 blockade combinatorial therapy in SCCFVII tumor-bearing C3H/HeOUJ mice undergoing intratumoral injections with RR-cyclic-di-guanine (synthetic CDG), CDG (natural cyclic-di-guanine), R848 (TLR 7/8 agonist), or phosphate buffered saline (PBS, control).



Intratumoral CDN treatment groups showed decreased tumor size and enhanced splenocyte Th1 response when compared to the PBS treatment control group (p < .05). The RR-CDG tumor microenvironment showed upregulated interferon (IFN)-γ+CD8+ and programmed death-L1. Combining programmed death-L1 blocking antibody with RR-CDG induced regression of established tumors.



This study demonstrates the antitumor effects of CDNs in a HNSCC cell line. These preclinical data strongly support the future clinical development of intratumoral CDN in patients with HNSCC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1086-1094, 2017.
Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Shekhar K
SK
Gadkaree
Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Juan
J
Fu
Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Rupashree
R
Sen
Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
Michael J
MJ
Korrer
Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Clint
C
Allen
Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
Young J
YJ
Kim
D000818:Animals; D000912:Antibodies, Neoplasm / Q000187:drug effects / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D008565:Membrane Proteins / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D061026:Programmed Cell Death 1 Receptor / Q000008:administration & dosage* / Q000276:immunology; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000077195:Squamous Cell Carcinoma of Head and Neck; D000099197:STING Protein
D000912:Antibodies, Neoplasm; D008565:Membrane Proteins; D061026:Programmed Cell Death 1 Receptor; C530855:Sting1 protein, mouse; D000099197:STING Protein
cyclic dinucleotide (CDN); cyclic-di-nucleotides; immunotherapy; squamous cell carcinoma; stimulator of interferon gene (STING)