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- Title
Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses.
- Authors
Malli Cetinbas, Naniye; Monnell, Travis; Soomer-James, Jahna; Shaw, Pamela; Lancaster, Kelly; Catcott, Kalli C.; Dolan, Melissa; Mosher, Rebecca; Routhier, Caitlin; Chin, Chen-Ni; Toader, Dorin; Duvall, Jeremy; Bukhalid, Raghida; Lowinger, Timothy B.; Damelin, Marc
- Abstract
Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs. Activation of the STING pathway can promote anti-tumor immunity. Here the authors generate tumor cell-directed STING agonist antibody-drug conjugates that activate STING in tumor and myeloid cells, promoting anti-tumor innate immune responses in preclinical cancer models.
- Subjects
ANTIBODY-drug conjugates; IMMUNE response; TYPE I interferons; MYELOID cells; ANTINEOPLASTIC agents; INTERFERONS; TUMORS; CXCR4 receptors
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49932-4