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Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

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Direct activation of STING in the tumor microenvironment partially overcomes immune tolerance in neu-N transgenic mice

STING signaling induces interferon-β production by intratumoral dendritic cells (DCs), driving T cell priming within the tumor microenvironment. However, the impact of antigen-specific tolerance on this process is not well studied. We therefore examined the efficacy of in situ tumor delivery of a potent STING-activating CDN ligand (ML-RR-S2 CDA) in both non-tolerant parental FVB/N and the immune tolerant neu-N transgenic mice bearing established HER-2+ breast tumors. In nontolerant FVB/N mice, single agent intratumoral ML-RR-S2 CDA injection induced complete tumor regression of both the injected tumor and a contralateral uninjected tumor, while also protecting mice from a subsequent tumor challenge. In contrast, intratumoral injection of ML-RR-S2 CDA alone in neu-N mice modestly delayed tumor growth. Furthermore, in contrast to our prior data that low dose cyclophosphamide could increase vaccine-induced immunity and tumor-free survival in neu-N transgenic mice, the sequential delivery of low dose cyclophosphamide with ML-RR-S2 CDA did not delay tumor outgrowth relative to ML-RR-S2 CDA alone. We therefore explored biomarkers of both STING pathway activation and T cell activity within the TME of FVB/N and neu-N transgenic mice. Intratumoral ML-RR-S2 CDA injection resulted in both high levels of IFNβ production in the TME of tumor bearing FVB/N mice, and the induction of a durable population of HER-2-specific CD8+ T cells. In contrast, intratumoral ML-RR-S2 CDA injection resulted in low levels of IFNb production in the TME of tolerant neu-N transgenic mice, and the induction of few HER-2-specific CD8+ T cells. Phenotypic analyses of tumor infiltrating leukocytes within the TME of untreated neu-N mice revealed increased expression of PD-1 on CD8+ T cells and PD-L1 on myeloid cells. Moreover, about 25% of HER-2+ tumor cells derived from the TME also expressed PD-L1. The addition of PD-L1 blockade to low dose cyclophosphamide in sequence with intratumoral ML-RR-S2 CDA resulted in a greater delay of tumor growth than intratumoral ML-RR-S2 CDA injection alone in neu-N transgenic mice, but did not clear any mouse of tumor. These findings suggest that multiple mechanisms of immune tolerance limit the ability of STING pathway activation to lead to HER-2 specific-CD8+ T cell activation and tumor regression in tolerant neu-N transgenic mice.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Foote, J., Leatherman, J.M., Amstrong, T.D. et al. Direct activation of STING in the tumor microenvironment partially overcomes immune tolerance in neu-N transgenic mice. j. immunotherapy cancer 3 (Suppl 2), P356 (2015).

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