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 Vaccines

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 3

MS-275 alters myeloid cell composition within the tumor and dLN and enhances costimulation.

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MS-275 alters myeloid cell composition within the tumor and dLN and enha...
Five days after treatment, digested tumors (n = 3 per group) were positively enriched for CD45.2 cells. (A) Representative scatter plots outlining the gating strategy for characterizing myeloid cell populations in the tumor and dLNs. SSC-A, side scatter area; FSC-A, forward scatter area. Myeloid cell composition changes in the tumor and dLNs during ACT with or without MS-275 treatment are depicted by (B and C) representative contour plots and (D and E) frequency as a percentage of total CD11c+ cells. Maturation marker expression levels in total CD11c+ cells in the (F) tumor and (G) dLN were determined by MHC class II– (I-Ab) and costimulatory ligand CD86–specific (B7-2–specific) flow staining. (H and I) Enriched CD11c+ cells were pulsed with LCMV GP33–41 peptide and cocultured with CFSE-labeled LCMV-P14 TCR-transgenic naive T cells. Representative histograms show CFSE dilution after 3 days, and changes in proliferation due to treatment were quantified using the division index. Data are presented as the mean ± SEM. *P < 0.05, ** P < 0.01, *** P < 0.001, and ****P < 0.0001, by Student’s t test (D–G) or 2-way ANOVA (I).