A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice

Jeremy B. Foote, Marleen Kok, James M. Leatherman, Todd D Armstrong, Bridget C. Marcinkowski, Lureen S. Ojalvo, David B. Kanne, Elizabeth Jaffee, Thomas W. Dubensky, Leisha A. Emens

Research output: Contribution to journalArticle

Abstract

Stimulator of interferon genes (STING) signaling induces IFNb production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigenspecific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2 breast tumors. ADU S-100 induced HER-2-specific CD8+ T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice. In contrast, ADU S-100 did not sufficiently prime HER-2- specific CD8+ T cells in tolerant neu/N mice, resulting in only delayed tumor growth and tumor clearance in 10% of the mice. No differences in IFNb production, DC priming, or HER-2- specific CD8+ T-cell trafficking were detected between FVB/N and neu/N mice. However, activation and expansion of HER-2- specific CD8+ T cells were defective in neu/N mice. Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8+ T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2-specific CD8+ T-cell activity, clearing tumors in 40% of neu/N mice. Thus, intratumoral STING agonists could potently prime tumor antigen-specific CD8+ T-cell responses, and adding PD-L1 blockade and OX40 receptor activation can overcome antigen-enforced immune tolerance to induce tumor regression.

Original languageEnglish (US)
Pages (from-to)468-479
Number of pages12
JournalCancer immunology research
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2017

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Foote, J. B., Kok, M., Leatherman, J. M., Armstrong, T. D., Marcinkowski, B. C., Ojalvo, L. S., Kanne, D. B., Jaffee, E., Dubensky, T. W., & Emens, L. A. (2017). A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice. Cancer immunology research, 5(6), 468-479. https://doi.org/10.1158/2326-6066.CIR-16-0284