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 M. 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

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OX40 Receptor
Interferons
Immunity
T-Lymphocytes
Genes
Neoplasms
Dendritic Cells
Programmed Cell Death 1 Receptor
Immune Tolerance
Tumor Microenvironment
Neoplasm Antigens
Myeloid Cells
Breast Neoplasms
Antigens

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice. / Foote, Jeremy B.; Kok, Marleen; Leatherman, James M.; Armstrong, Todd D.; Marcinkowski, Bridget C.; Ojalvo, Lureen S.; Kanne, David B.; Jaffee, Elizabeth M.; Dubensky, Thomas W.; Emens, Leisha A.

In: Cancer Immunology Research, Vol. 5, No. 6, 01.06.2017, p. 468-479.

Research output: Contribution to journalArticle

Foote, Jeremy B.; Kok, Marleen; Leatherman, James M.; Armstrong, Todd D.; Marcinkowski, Bridget C.; Ojalvo, Lureen S.; Kanne, David B.; Jaffee, Elizabeth M.; Dubensky, Thomas W.; Emens, Leisha A. / A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice.

In: Cancer Immunology Research, Vol. 5, No. 6, 01.06.2017, p. 468-479.

Research output: Contribution to journalArticle

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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.",
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AU - Ojalvo,Lureen S.

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AU - Dubensky,Thomas W.

AU - Emens,Leisha A.

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