HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity
Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan
Andrew Nguyen, Louisa Ho, Richard Hogg, Lan Chen, Scott R. Walsh, Yonghong Wan
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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.