Intratumoral administration of S100 – a STING agonist currently in clinical trials – at relatively low, but not high, doses led to rejection of injected tumors and durable immune protection. Mechanistically, hematopoietic cells contributed to STING signaling, and intratumoral monocytes produced STING pathway cytokines IFNβ and TNFα; type I IFN, but not TNFα, was required for CD8+ T cell activation and tumor control. Combination of low-dose S100 with anti-PD-1 and/or anti-CTLA-4 eliminated both injected and non-injected tumors and increased survival. High doses of S100 ablated the injected tumors, but resulted in poor immunological memory.

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, TNFalpha 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.

Author Info: (1) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (2) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (3) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (4)

Author Info: (1) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (2) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (3) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (4) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (5) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (6) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (7) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (8) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (9) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (10) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (11) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (12) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (13) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (14) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (15) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (16) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (17) Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. (18) Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. (19) Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. (20) Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA. (21) Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA. (22) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (23) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (24) Aduro Biotech, Inc., Berkeley, CA 94710, USA. (25) Aduro Biotech, Inc., Berkeley, CA 94710, USA. Electronic address: smcwhirter@aduro.com.

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