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Supplementary Figure S8. An intact adaptive immune response is necessary for efficacy triple therapy in neu/N mice. from A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice

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posted on 2023-04-03, 23:23 authored by Jeremy B. Foote, Marleen Kok, James M. Leatherman, Todd D. Armstrong, Bridget C. Marcinkowski, Laureen S. Ojalvo, David B. Kanne, Elizabeth M. Jaffee, Thomas W. Dubensky, Leisha A. Emens

(A) Tumor bearing neu/N mice were treated with isotype control (gray line) αCD4 (dashed gray line), αCD8 (dashed black line), or αCD4 + αCD8 (dotted black line) depleting antibodies. Depletion was initiated a week prior to NT2.5 tumor implantation and carried out with biweekly IP injections for the duration of the study. Depletion efficacy of 90% was confirmed before NT2.5 tumor implantation and upon completion of the study. As previously described mice were treated with IT ADU-S100 in sequence with αOX40 receptor agonistic and αPD-L1 antagonistic antibodies. Untreated tumor-bearing neu/N mice were included as control (black line). Tumor growth was followed for 35 days. (B) Serum from tumor-bearing neu/N mice receiving mock or ADU-S100 IT injection sequenced with either αOX40 receptor agonistic and αPD-L1 antagonistic antibodies or isotype matched controls was harvested 7 days post IT injection and HER-2 specific IgG antibody was measured. (C) HER-2-specific IgG antibody was measured in the cohorts of mice from figure (A) 7 days after IT-ADU-S100 injections. Statistical significance was determined through one-way Anova with significant differences in means re-evaluated using Bonferroni post-test. All data is cumulative of 2 - 3 experiments of 5 mice/group. * p < 0.05, ** p<0.01, and *** p<0.001, and **** p<0.0001.

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Breast Cancer Research Foundation

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ARTICLE ABSTRACT

Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific 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 IFNβ 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. Cancer Immunol Res; 5(6); 468–79. ©2017 AACR.