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Magnitude of Therapeutic STING Activation Determines CD8<sup>+</sup> T Cell-Mediated Anti-tumor Immunity

Mckenna, Jeffrey and Feng, Yan and Zheng, Lianxing and Bender, Steven and Cho, Charles and McWhirter, Sarah and Dubensky, Thomas and van Elsas, Andrea and Ndubaku, Chudi and Sivik, Kelsey and Desbien, Anthony and Hix-Glickman, Laura (2018) Magnitude of Therapeutic STING Activation Determines CD8<sup>+</sup> T Cell-Mediated Anti-tumor Immunity. Cell reports, 25 (11). p. 3074. ISSN 22111247

Abstract

STING pathway activation by intratumoral administration of cyclic dinucleotides (CDNs) results in stable tumor regression, yet the underlying innate and adaptive immune mechanisms are not fully established. ADU-S100, CDN under clinical evaluation, was used with an optimized dosing regimen to uncover key immune requirements for tumor regression. An immunogenic dose induces local expansion of tumor-specific CD8+ T cells, which are both necessary and sufficient for durable anti-tumor immunity and correlated with STING activation in hematopoietic but not tumor or stromal cells. Type I IFN, but not TNFα, drives optimal anti-tumor immune responses. The function of ADU-S100-induced CD8+ T cells was enhanced by combination with immune checkpoint modulators anti-PD-1 and anti-CTLA4. These results provide fundamental mechanistic insights into STING IT therapy.

Item Type: Article
Date Deposited: 25 Dec 2018 00:45
Last Modified: 25 Dec 2018 00:45
URI: https://oak.novartis.com/id/eprint/35866

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