Supplementary Figure S2. ADU-S100 induces apoptosis and necrosis of established tumors in tumor bearing, non-tolerant FVB/N and tolerant neu/N mice. from 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, Laureen S.; Kanne, David B.; Jaffee, Elizabeth M.; Dubensky, Thomas W.; Emens, Leisha A.

doi:10.1158/2326-6066.22539332.v1

Supplementary Figure S2. ADU-S100 induces apoptosis and necrosis of established tumors in tumor bearing, non-tolerant FVB/N and tolerant neu/N mice. from A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice

journal contribution

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-B) Tumor-bearing FVB/N and neu/N mice were treated with 1 dose of ADU-S100, and 24 hours later (A) necrotic tumor cells were evaluated by hematoxylin and eosin staining. (B) The surface area of necrosis in ADU-S100- and HBSS-treated FVB/N and neu/N mice was scored. At 24 hours post IT injection of ADU-S100 or HBSS numbers of activated caspase 3+ cells were evaluated by hematoxylin and eosin in FVB/N and neu/N mice. (C) A representative stain for active caspase 3 is shown for an ADU-S100 tumor from FVB/N mouse. (D) Relative active caspase 3 scored from treated FVB/N and neu/N mice are shown. Data is representative of 3 independent experiments of 5 mice/group. * p < 0.05, ** p<0.01, and *** p<0.001, and **** p<0.0001.

Funding

Breast Cancer Research Foundation

NIH

NCI

History

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.