Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non-Muscle Invasive Murine Bladder Cancer.

Abstract

Stimulator of interferon genes (STING) is an innate immune receptor activated by natural or synthetic agonists to elicit antitumoral immune response via type I IFNs and other inflammatory cytokines. Bacillus Calmette-Guerin (BCG) is the standard of care as intravesical therapy for patients with high-risk non-muscle invasive bladder cancer (NMIBC). There are limited options available for patients with NMIBC who developed BCG unresponsiveness. In this study, we characterized in vitro and in vivo antitumor effects of E7766, a macrocyle-bridged STING agonist, via intravesical instillation in two syngeneic orthotopic murine NMIBC tumor models resistant to therapeutic doses of BCG and anti-PD-1 agents. E7766 bound to recombinant STING protein with a Kd value of 40 nmol/L and induced IFNβ expression in primary human peripheral blood mononuclear cells harboring any of seven major STING genotypes with EC50 values of 0.15 to 0.79 μmol/L. Intravesical E7766 was efficacious in both NMIBC models with induction of effective immunologic memory in the treated animals. Pharmacologic activation of the STING pathway in the bladder resulted in IFN pathway activation, infiltration of T cells and natural killer (NK) cells, dendritic cell activation, and antigen presentation in bladder epithelium, leading to the antitumor activity and immunity. In addition, measurements of the pharmacodynamic markers, Ifnβ1 and CXCL10, in bladder, urine, and plasma, and of STING pathway intactness in cancer cells, supported this mode of action. Taken together, our studies reveal an antitumor immune effect of pharmacologic activation of the STING pathway in bladder epithelium and thus provide a rationale for subsequent clinical studies in patients with NMIBC.

• Authors: Kuan-Chun Huang, Dinesh Chanda, Shannon McGrath, Vaishali Dixit, Chi Zhang, Jiayi Wu, Karen Tendyke, Huilan Yao, Renee Hukkanen, Noel Taylor, David Verbel, Dae-Shik Kim, Atsushi Endo, Thomas A Noland, Yu Chen, Mark Matijevic, John Wang, Janna Hutz, Nadeem Sarwar, Francis G Fang, Xingfeng Bao
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 6 Pg. 914-924 (06 01 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 35313332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• BCG Vaccine
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• BCG Vaccine (pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Humans
• Leukocytes, Mononuclear (metabolism)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Urinary Bladder (metabolism, pathology)
• Urinary Bladder Neoplasms (drug therapy, pathology)