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 1

Concomitant MS-275 delivery prevents tumor relapse during ACT.

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Concomitant MS-275 delivery prevents tumor relapse during ACT. In C57BL/...
In C57BL/6 mice (n = 5 per group), (A) 5-day-old intradermal B16-gp33 tumors were treated with ACT (104 LCMV GP33–41–specific Tmem cells delivered i.v. followed by viral vaccination). MS-275 was injected i.p. daily for 5 days starting at various time points. Tumor volumes were calculated on the basis of tumor height, width, and length. (B) IF staining for anti–cleaved caspase 3 antibody and TO-PRO-3 nuclear staining (scale bars: 25 μm), (C) H&E staining (scale bars: 10 μm), and (D) IHC anti-CD8 antibody staining (scale bars: 25 μm) of frozen tumor sections harvested 5 days after treatment. Digested tumors (n = 5 per group) were enriched for CD45.2+ cells, and the (E) frequency of CD45.2+CD8+ T cells and (F) absolute count of LCMV GP33–41–specific CD8+ T cells as determined by IFN-γ expression after ex vivo peptide stimulation were measured. (G) Tumor volume measurements following selective lymphocyte depletion prior to and during ACT+MS-275 treatment using mAbs specific for CD8, CD4, and NK1.1. Data are presented as the mean ± SEM . ****P < 0.0001, by 1-way ANOVA. No Tx, no treatment.