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 <p>In untreated, tumor bearing FVB/N and neu/N mice intratumoral chemokine gradients were evaluated by multiplex ELISA. FVB/N express increased amounts of CXCL9, CCL3, CCL4, and CCL5, whereas neu/N mice express increased amounts of CCL2. Data is representative of 3 independent experiments involving 5 mice/group. Statistical significance was determined by multiple students'' t-test and a Bonferroni-Dunn posttest was performed to correct for increasing type I error. * p < 0.05, ** p<0.01, and *** p<0.001, and **** p<0.0001.</p>
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.
