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Cell Rep. 2018 Dec 11;25(11):3074-3085.e5. doi: 10.1016/j.celrep.2018.11.047.

Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity.

Author information

1
Aduro Biotech, Inc., Berkeley, CA 94710, USA.
2
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
3
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
4
Aduro Biotech, Inc., Berkeley, CA 94710, USA. Electronic address: smcwhirter@aduro.com.

Abstract

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.

KEYWORDS:

ADU-S100; CD8(+) T cell; ImmunoOncology; STING; abscopal immunity; anti-tumor immunity; checkpoint inhibitor; cyclic dinucleotide; intratumoral; type I interferon

PMID:
30540940
DOI:
10.1016/j.celrep.2018.11.047
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