HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity
Andrew Nguyen, … , Scott R. Walsh, Yonghong Wan
Andrew Nguyen, … , Scott R. Walsh, Yonghong Wan
Published August 16, 2022
Citation Information: J Clin Invest. 2022;132(19):e159283. https://doi.org/10.1172/JCI159283.
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Research Article Immunology

HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity

Abstract

Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor–associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.

Authors

Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan

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Figure 2

MS-275 remodels the inflammatory landscape of the TME to promote antigen processing and presentation.

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MS-275 remodels the inflammatory landscape of the TME to promote antigen...
Bulk tumor RNA was derived from ACT-treated mice with or without MS-275 for microarray analysis (n = 4 per group). (A) Heatmap and GSEA of custom gene sets representing specific inflammatory pathways on day 1 and day 5 (see also Supplemental Table 2). (B) qRT-PCR of proinflammatory cytokines at specific time points after treatment (n = 3 per group). (C) GSEA of curated gene sets (C2) derived from the MSigDB and displayed as an enrichment map (see also Supplemental Figure 2). (D) GO analysis of modules (see also Supplemental Table 3) derived from DEGs (day 3 vs. day 1 and day 5 vs. day 1; FDR P < 0.05) within a PPI network. Modules were sorted by the ratio of upregulated to downregulated genes when comparing ACT+MS-275 with ACT alone (see also Supplemental Figure 3). (E) qRT-PCR of myeloid-related chemokines at specific time points after treatment (n = 3 per group). (F) GSEA of immunologic signatures (C7) derived from the MSigDB, where highlighted groups represent gene sets related to activated myeloid cells (see also Supplemental Figure 4). *FDR P < 0.05 (A, C, and F). Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired Student’s t test (B and E).