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Supplementary Figure S3. Gene expression in ADU-S100 treated tumors from 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) 162 differentially expressed genes (Affymetrix Mouse Gene 2.0 ST array, 3 independent experiments, ANOVA p<0.05 and at least 2 fold change) induced by ADU-S100 IT injection on day 1 in tolerant neu/N mice. (B) The five most significant canonical pathways (Ingenuity Pathway Analysis) enriched 1 day after ADU-S100 IT injection in tolerant neu/N mice. P-values calculated using Fisher''s exact test. The orange points represent the ratio between the number of genes induced by IT ADU-S100 that belong to that specific pathway by the total number of genes annotated to that specific pathway. (C) Average mRNA values of C-C chemokines and CXC chemokines 1 and 7 days after IT ADU-S100 in tolerant neu/N mice. P-values calculated using ANOVA.

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Breast Cancer Research Foundation

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NCI

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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.

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    Cancer Immunology Research

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    Breast CancerCancer PreventionAnimal models of preventionImmunologyCytokinesImmune responses to cancerImmunomodulationTumor antigens/neoantigensTumor resistance to immune responseImmunotherapyCancer vaccines

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