Abstract 1202: Tumor cell intrinsic STING signaling demonstrates minimal contribution to the anti-tumor response elicited by the STING agonist ADU-S100 (MIW815)
Authors: Corrales Leticia , Desbien Antony L. , Gauthier Kelsey E. Sivick , Deng Weiwen , Schroeder Tamara , Reiner Gabrielle L. , Surh Natalie , Francica Brian , Metchette Ken , Ndubaku Chudi O. , McKenna Jeffrey M. , Feng Yan , Zheng Lianxing , Bender Steven L. , Cho Charles Y. , Elsas Andrea van , Leong Meredith L. , McWhirter Sarah M. 
Published: August 2019

Innate immune sensing of tumors is a critical step in generating spontaneous anti-tumor T cell responses. Endogenous activation of the STING pathway in immune cells and the subsequent generation of type I IFN is sufficient to generate spontaneous anti-tumor T cell responses. To take advantage of this tumor defense mechanism for therapeutic intervention, Aduro has developed the first-in-class STING agonist, ADU-S100 (MIW815), a small molecule derivative of the natural cyclic dinucleotide STING ligand. In mouse models, intratumoral administration of ADU-S100(MIW815) increases systemic tumor-specific T cells and results in substantial antitumor efficacy. ADU-S100 (MIW815) is currently being tested as mono- or combination therapy in Phase 1 clinical studies enrolling patients with cutaneously-accessible treatment-refractory advanced solid tumors and lymphomas. STING is broadly expressed across different cell types, however several studies have demonstrated that tumor cells regulate expression of STING and other members of the pathway, mainly cGAS, by epigenetic mechanisms. Activation of the STING pathway in innate immune cells is necessary for the generation of anti-tumor T cell responses, but the role of other cell types within the tumor microenvironment in response or resistance to STING agonists is not completely understood. To understand the contribution of tumor-cell STING to the anti-tumor response, we generated STING-deficient 4T1 tumor cells using the CRISPR/Cas9 system. Composition of the tumor microenvironment, endogenous T cell responses and tumor growth were comparable in animals with implanted STING-WT or -KO tumor cells. Similar data was observed in the B16.SIY melanoma model. In order to understand the role of tumor-STING in the context of ADU-S100 (MIW815) treatment, animals implanted with 4T1 STING WT or KO tumor cells were treated with a wide range of ADU-S100 doses. Expression of STING within tumor cells did not impact activation of innate cells or generation of tumor-specific T cells among all the tested doses. At immunogenic doses, tumor cell expression of STING was not required for tumor growth control.Overall, these results show that ADU-S100 (MIW815) activation of STING in host cells rather than in tumor cells is critical for production of type I interferon and tumor control. This supports potential treatment of cancers of different histologies regardless of tumor cell-intrinsic STING expression.

Citation Format: Leticia Corrales, Antony L. Desbien, Kelsey E. Sivick Gauthier, Weiwen Deng, Tamara Schroeder, Gabrielle L. Reiner, Natalie Surh, Brian Francica, Ken Metchette, Chudi O. Ndubaku, Jeffrey M. McKenna, Yan Feng, Lianxing Zheng, Steven L. Bender, Charles Y. Cho, Andrea van Elsas, Meredith L. Leong, Sarah M. McWhirter. Tumor cell intrinsic STING signaling demonstrates minimal contribution to the anti-tumor response elicited by the STING agonist ADU-S100 (MIW815) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1202.