TY - JOUR
T1 - A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice
AU - Foote, Jeremy B.
AU - Kok, Marleen
AU - Leatherman, James M.
AU - Armstrong, Todd D.
AU - Marcinkowski, Bridget C.
AU - Ojalvo, Lureen S.
AU - Kanne, David B.
AU - Jaffee, Elizabeth M.
AU - Dubensky, Thomas W.
AU - Emens, Leisha
N1 - Funding Information:
This work is in part supported by Breast Cancer Research Foundation Grant #116656 (L.A. Emens and E.M. Jaffee), NIH T32RR07002-37 (J.B. Foote), and NCI P30CA006973.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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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U2 - 10.1158/2326-6066.CIR-16-0284
DO - 10.1158/2326-6066.CIR-16-0284
M3 - Article
C2 - 28483787
AN - SCOPUS:85020641723
SN - 2326-6066
VL - 5
SP - 468
EP - 479
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 6
ER -